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January 1999
Pharmacokinetic Considerations in Obesity
Contribution from Division of Pharmaceutical Sciences, College of Pharmacy and Graduate Center for Toxicology, University ofKentucky, Lexington, Kentucky 40536-0082. Final revised manuscript received October 26, 1998.
Accepted for publication October 28, 1998.
There have been several references reviewing the causes and pharmacological implications of obesity.6-12 These Obesity is a disease characterized as a condition result- show the effects of obesity on the pharmacokinetics of drugs ing from the excess accumulation of body fat. In conjunction in obese subjects; however, there have been considerable with increased stores of body fat, obesity has also been advances in the understanding of obesity, particularly in associated with increased mortality influenced by increased the genetic causes and changes in genetic expression incidence of hypertension, atherosclerosis and coronary asssociated with obesity. This article will attempt to artery disease, diabetes, cancers of the breast, colon, comprehensively review current knowledge regarding obe- prostate, endometrium, ovary, and cervix, and decreased sity ranging from genetic and nutritional animal studies overall survivability when compared with nonobese to pharmacokinetic studies of specific drugs in humans.
counterparts.1-5 As a consequence, obese individuals gen-erally require more therapeutic intervention earlier in lifethan nonobese individuals. A very important consideration Obesity and Drug Absorption
for pharmacological treatment of obese individuals is thepossible discrepancies between obese and nonobese indi- The effects of obesity on absorption and overall bioavail- viduals in pharmacokinetic and/or pharmacodynamic ac- ability is poorly understood. In contrast to expected de- tivities of a drug. Changes in pharmacokinetic parameters creases in bioavailability associated with increased splanch- such as volume of distribution or clearance can significantly nic blood flow in obesity,23 the bioavailability of midazolam13 alter the pharmacologic impact of a drug; therefore, it is and propanolol,14 two compounds with moderate to high important to characterize the properties of drugs in obese hepatic extraction, was shown not to be significantly different between obese and lean individuals. Body weightwas shown to have no effect on the bioavailability of The direct causes of obesity are difficult to discern due cyclosporine in renal transplant recipients.15 No statisti- to the plethora of physiological changes associated with cally significant difference in the bioavailability of dexfen- obesity. Furthermore, characterizing metabolic and genetic fluramine could be established between obese and normal- differences between obese and nonobese individuals has weight individuals.16 Overall, studies indicate no significant proven complex resulting in broad scale attempts to study difference in absorption between obese and lean subjects.
genetic and nutritional models of obesity in animals. Theseanimal models can be used to help determine the possiblecauses and effects of obesity in humans resulting in Obesity and Drug Distribution
possible agents to attenuate the causes and effects ofobesity.
The volume of distribution of a drug is dependent on a number of factors including tissue size, tissue permeability,plasma protein binding, and the affinity of drugs for a * Corresponding author: Tel: 606-257-5736. Fax: 606-257-7564.
tissue compartment.17 These factors can be affected by the 1999, American Chemical Society and Journal of Pharmaceutical Sciences / 1
American Pharmaceutical Association physical and chemical properties of a drug in addition to have volumes of distribution that decrease when corrected the presence of many disease states. Obesity is a disease for TBW.42,43 These decreased volumes of distribution when state associated with changes in plasma protein binding corrected for TBW indicate that these drugs distribute less constituents18,19 and increases in adipose tissue mass and into excess adipose tissue. Bisoprolol was shown to have lean body mass,20 organ mass,21,22 cardiac output,23,24,25 an increased apparent volume of distribution but decreased cardiac size and blood volume,23,24 and splanchnic blood volume when corrected for TBW. The authors concluded flow23 relative to normal-weight individuals.
that these parameters indicated that bisoprolol distributed A general trend has been observed for predicting changes primarily into excess lean body mass relative to excess in volume of distribution in obese subjects. Increasingly lipophilic substances, based upon the octanol/water lipid Plasma protein binding is an important determinant of partitioning coefficients (LPC), are generally increasingly a drugs pharmacokinetics. Changes in the concentrations affected by obesity. Less lipophilic compounds, with lower of plasma binding proteins or alterations in the affinity of LPCs, generally have little to no change in volume of plasma proteins for substrate could affect the movement distribution with obesity. There are exceptions to this of drug into tissue compartments. The major plasma generalization: cyclosporine, a highly lipophilic compound proteins are albumin, primarily responsible for binding with a relatively large volume of distribution, has been acidic drugs, R1-acid glycoprotein (AAG), primarily respon- shown in separate experiments to have comparable abso- sible for binding basic drugs, and lipoproteins. Studies have lute volumes of distribution (Vdss) in both obese and normal- shown that drugs primarily bound by albumin (e.g., thio- pental27 and phenytoin18,19,44) show no significant changes The effect of high lipid partition coefficients in barbitu- in protein binding in obese individuals; however, the rates was demonstrated by Cheymol8 when increasing LPC binding of drugs to AAG have been shown to increase and were correlated with increases in distribution into adipose decrease in obesity. Benedek et al.19 showed a significant tissue. Thiopental27 and diazepam,11,28 with corresponding increase in AAG concentrations in obese individuals with LPC values of 67629 and 309,30 show significant increases concomitant decreases in the free fractions of propanolol, in volume of distribution (Vdss) for obese individuals relative principally bound by AAG. Cheymol et al.45 showed no to normal-weight individuals. In both cases, the volume of significant differences in AAG between obese and lean distribution increased for both absolute volume of distribu- individuals; however, a decrease in volume of distribution tion and when normalized for total body weight. However, of propanolol was observed which was more consistent with the absolute distribution (Vdss) of digoxin31 and procain- increased plasma protein binding. Derry et al.46 also amide32 has been shown to remain relatively consistent observed an increase in AAG with no change in the plasma between obese and normal-weight individuals despite free fraction of triazolam, a drug principally bound by AAG.
relatively high LPC values,29,33 and the distribution of These results indicate the possibility that plasma protein digoxin decreased in obese individuals when normalized binding affinity may change in obesity without changes in to actual body weight.31 Others have shown that digoxin protein concentrations. The plasma protein binding of does not have extensive distribution into adipose tissue.34 verapamil, also associated with AAG binding, was un- These results are supportive of the explanation by Christoff changed between obese and nonobese individuals.47 Due et al.32 that the high LPC values are too low to enhance to higher triglyceride and cholesterol levels common in distribution into adipose tissue. Ritschell and Kahl33 have obesity, lipoprotein levels may be elevated in obese indi- developed equations based upon several parameters (i.e., viduals; however the ramifications of elevated lipoprotein LPC, plasma protein binding, ionization, normal-weight levels has been poorly studied and is not well understood volume of distribution, and body weight parameters) to help determine volume of distribution in obese individuals, The clearance of drugs can also be affected by obesity, but there has been little further experimental support of though increases in clearance do not necessarily reflect changes in the half-life of a drug. The half-life of a drug Polar compounds have been shown to have several can be related to both volume of distribution and clearance different relationships between body weight and volume of distribution. Theophylline, shown not to correlate wellwith ideal body weight (IBW) or total body weight (TBW),35,36 was shown to adhere well to the following power equationsuggested by Rizzo et al.:37 The half-life of a drug may increase without changes in clearance. Abernathy et al.48 showed a significant increase in the plasma half-life of desmethyldiazepam without changes in clearance. Rather, the change in half-life was Several authors38,39 agree that a better relationship attributed to the increase in volume of distribution in obese between aminoglycoside volume of distribution and body individuals. LeJeunne et al.42 demonstrated increased weight is given in the following equation proposed by Bauer absolute volume of distribution (Vdss) and increased clear- ance of bisoprolol with no change in plasma half-life inobese versus nonobese individuals. These studies demon-strate the interrelationships between half-life, volume of V (in liters) ) (0.26 L/kg)[IBW + (CF × AW)] distribution, and clearance as well as indicates the useful-ness of volume of distribution and clearance over plasma where CF is a correction factor between 0.2 and 0.5 and Neuromuscular agents are another group of generally polar compounds. The best method of calculating dosing Obesity and Drug Clearance
strategies might be to base calculations on IBW. In onestudy, it was shown that the absolute volume of distribu- Changes in Metabolic Enzymes in Obese Humanss
tion (Vdss) of atracurium is unchanged in obese individu- Measuring changes in hepatic metabolizing enzymes in als.41 At the same time, the volume of distribution corrected humans is difficult due to the general lack of enzyme for TBW decreased. Some lipophilic substances, such as the specific markers of metabolic activity. As a result, relation- -adrenergic receptor blockers bisoprolol and nebivolol, also ships are usually drawn between pharmacokinetic behavior 2 / Journal of Pharmaceutical Sciences
of a drug in humans and measured metabolic enzyme levels Using drugs that are primarily transformed via Phase in animals. Important considerations are presented by the II conjugation pathways, glucuronidation and sulfation fact that fatty infiltration characterizes the livers of most have been shown to increase in obese individuals. The individuals.49 This fatty infiltration generally resembles clearance of oxazepam and lorazepam, benzodiazepines mild alcoholic hepatitis in moderately obese individuals,49 excreted primarily in the form of glucuronide conjugates, but morbidly obese individuals have markedly increased was shown to increase in obese individuals.54 In another liver damage.50 These factors could have a significant study, acetaminophen clearance was shown to increase impact on the metabolic activity of the liver thereby with obesity,55 though not as significantly as the increases dictating the importance of characterizing metabolism in shown with oxazepam and lorazepam.54 It has been shown obese individuals. There are some determinants of meta- that acetaminophen is eliminated as both a glucuronide bolic activity in humans that are generally considered as and sulfate conjugate in humans56 whereas oxazepam and definitive markers for enzyme levels that have been used lorazepam are excreted primarily as glucuronide conju- to show differences between obese and normal-weight gates. It is likely that obesity affects different pathways individuals. These markers and the effects of obesity are through different mechanisms and levels: where glucu- discussed in the following paragraphs. Unless stated ronidation might be significantly enhanced, sulfation may otherwise, clearance parameters are not normalized for only be slightly to moderately enhanced due to obesity.
Other evidence supporting differential regulation of It was previously thought that hepatic oxidative me- Phase II pathways are studies showing that the clearance tabolism was essentially unchanged in the obese individual of salicylate57 and procainamide32 is not significantly when compared to a normal-weight individual. Caraco et different between obese and lean individuals. Salicylate is al.51 used obese and lean volunteers to evaluate the conjugated to the glycine, phenolic, and acyl glucuronide, pharmacokinetics of antipyrine, a marker for hepatic and procainamide is primarily acetylated. Together these oxidative metabolism. In the obese group, plasma half-life results indicate that these pathways may not be signifi- increased, apparent volume of distribution increased (but cantly affected by obesity in humans.
decreased when corrected for TBW), and the clearance Another interesting consideration in determining the remained unchanged. When volunteers were enrolled in a metabolic activity of obese individuals is considering weight reduction program, obese individuals showed de- changes in metabolism in tissues other than the liver; creased half-life, decreased volume of distribution (in- specifically, due to the significant increase in adipose tissue creased when corrected for TBW), and a nonsignificant in obese individuals, changes in metabolism within adipose increase in clearance after losing weight. The nonsignifi- tissue could be significant. Rafecas et al.,58 using white cant changes in clearance indicate that the oxidative adipose tissue from obese and lean patients, observed an pathways employed by the liver for antipyrine metabolism increase in insulin cleavage in obese subjects relative to remain unchanged between obese and normal-weight normal-weight subjects. In the absence of reduced glu- individuals; however, antipyrine undergoes extensive he- tathione, no insulin was cleaved, indicating that glu- patic oxidative metabolism through multiple oxidative tathione transhydrogenase, present in white adipose tissue, pathways, and a change in singular pathways would be was likely the only enzyme responsible for insulin cleavage within white adipose tissue. The authors stated that Metabolism of chlorzoxazone to 6-hydroxychlorzoxazone hyperinsulinemia common in obesity may be offset by the has been used as a marker for hepatic cytochrome P450 substantial increase in adipose tissue possessing high (CYP) 2E1 activity in humans. O′Shea et al.94 showed intrinsic insulin cleaving activity. The results of this study increased chlorzoxazone clearance in obese individuals as point to the possibility that adipose tissue might play a well as increased formation clearance of 6-hydroxychlor- significant role in energy regulation in obese individuals.
zoxazone from chlorzoxazone. The increase in chlorzox- Further evidence suggests that adipose tissue may play a azone clearance was attributed to increased CYP2E1 role in the increased clearance of prednisolone in obese activity associated with obesity. The authors further stated men.59 The interconversion of prednisolone and prednisone that the increase in CYP2E1 activity may predispose obese is dependent on 11-hydroxysteroid dehydrogenase, an individuals to CYP2E1-mediated toxicities associated with enzyme present in adipose tissue; therefore, the increase the production of toxic metabolites from environmental in adipose tissue may provide an alternative site of The formation of 6 -hydroxycortisol and N-methyleryth- In a series of studies, the pharmacokinetics of carbam- romycin from cortisol and erythromycin has been shown azepine was evaluated in obese subjects before and after to provide a general marker for cytochrome P450 3A significant weight reduction60 and in obese versus lean activity in humans.52,53 Hunt et al.52 performed a study in subjects.61 In the first study, obese subjects were monitored volunteers to monitor the metabolism of cortisol and to establish the pharmacokinetic parameters of carbam- erythromycin to 6 -hydroxycortisol and N-methylerythro- azepine, and then each subject was entered into a weight mycin. Using these parameters as measures of CYP3A reduction program, regulating diet and exercise, after activity in humans, it was found that a negative correlation which the same pharmacokinetic parameters were assessed existed between percent IBW and N-methylerythromycin and compared for each individual. After significant weight production. In contrast, cortisol metabolism showed no reduction, the formerly obese individuals had a decreased negative correlation between percent IBW and urinary 6 - plasma half-life, increased clearance, decreased absolute hydroxycortisol/cortisol ratios. The authors thought that volume of distribution (Varea) with respect to bioavailabil- similar correlations should be drawn between percent IBW ity, and no significant change in Varea when normalized and N-methylerythromycin and percent IBW and 6 - for total body weight. In the second study, relative to hydroxycortisol/cortisol ratios. Another study by Hunt et normal-weight individuals, obese individuals had increased al.53 supported changes in CYP activity in humans by absolute volume of distribution (Varea), increased plasma showing a negative correlation between erythromycin half-life, and unchanged clearance values. The disparity N-demethylation and percent IBW in elderly subjects.
between changes in clearance remains unexplained, but it These contrasting studies demonstrate the difficulties is important to note that obesity may be associated with associated with correlations between specific markers of changes in blood flow or metabolic activity. Further com- drug metabolism and specific CYP isoform modulation.
parison between the two studies indicates that, for car- Journal of Pharmaceutical Sciences / 3
bamazepine, the increased volume of distribution and half- be altered resulting in differential pharmacotherapeutic life associated with obesity may involve reversible processes effects in obese individuals as compared to lean individuals.
that may disappear following weight reduction.
Changes in Metabolic Enzymes in Obese Animals
Changes in Renal Function in Obese Humans
The influence of pathophysiologic and morphologic Elimination of a drug through the kidney can be ac- changes associated with obesity on hepatic metabolism is counted for by glomerular filtration, tubular secretion, and not well understood. Before the late 1980s, studies cor- tubular reabsorption; however, there are several discrep- relating obesity-associated changes with either hepatic ancies regarding the influence of obesity on these functions.
drug metabolizing enzymes (e.g., hepatic cytochrome P450) Davis et al.62 and Stockholm et al.63 have independently or drug markers (e.g., antipyrine) were nonexistent. In shown increases in glomerular filtration, measured using 1989, Corcoran et al.12 showed no significant difference in creatinine clearance, in obese women as compared to CYP concentrations between obese and lean rats; however, normal-weight women. Dionne et al.64 has also shown total CYP increased per liver in the obese overfed rat.
increased creatinine clearance in obese subjects when Beginning in the early 1990s, studies began showing compared to historical values of creatinine clearance; changes in hepatic CYP resulting from obesity using both however, Ducharme et al.65 showed decreased glomerular animal models and human markers. Studies dating as far filtration via creatinine clearance in obese individuals from back as the 1970s have indicated changes in Phase II a patient population study of vancomycin pharmacokinet- metabolism pathways associated with obesity. The follow- ics. Reiss et al.66 and Allard et al.67 showed no significant ing paragraphs describe differences in Phase I and Phase difference between creatinine clearance in obese versus II metabolism in obese animal models.
nonobese individuals. There are also discrepancies between Research has been conducted to determine the effects of studies of drug primarily excreted by glomerular filtration.
either genetically or nutritionally induced obesity in mice Historical evidence has shown that the aminoglycoside and rats. Irizar et al.76 observed decreased total CYP antibiotics68 including gentamicin69,70 and vancomycin71 are expression in genetically obese (fa/fa) Zucker rats. When associated with increased clearance in obese individuals; expressed as CYP activities per nmol of total CYP, CYP1A, however, recent evidence has shown that vancomycin CYP2B, CYP2E, CYP3A, and CYP4A were shown to clearance is unchanged in obese individuals greater than increase in obese rats using specific substrates. Absolute 1.3 times their IBW.64 One possible explanation for these CYP activities increased for CYP1A and CYP3A in obese discrepancies might be due to the difference in extent of rats whereas the increase in expression of other CYP obesity and/or associated renal pathology.
isoforms resulted primarily due to the decrease in overall Tubular function (i.e., tubular secretion and tubular CYP levels. Anti-mouse CYP2D antibodies showed a de- reabsorption) in the kidney is often difficult to ascertain; crease in apoprotein in obese rats when compared with thus, conclusions regarding tubular function are often normal rats. The investigators indicated the possibility that indirect. Changes in tubular function have been indicated reduced growth hormone (reduced in obese male animals in several studies. The renal clearance of ciprofloxacin,67 and shown to be partially responsible for the regulation of cimetidine,72,73 procainamide,32,45 and lithium66 has been CYP3A expression) caused the increase in CYP3A activity.
shown to increase in obese individuals. Since the renal These results illustrate the possible ramifications of geneti- excretion of ciprofloxacin,92 cimetidine,95 and procaina- cally induced obesity; however, parallels to humans are mide32 involves primarily glomerular filtration and tubular difficult to establish due to difficulty in characterizing the secretion, the increases in renal clearance of ciprofloxacin, genetic causes of obesity in humans.
cimetidine, and procainamide accompanied by a dispro- An alternative model of obesity uses nutritional modula- portionate increase in glomerular filtration supports in- tion to induce obesity. Salazar et al.79 previously reported creased tubular secretion in obese individuals. Renal an increase in CYP2E1 in obese overfed rats. Raucy et al.77 clearance of lithium primarily involves glomerular filtra- used overfed Sprague Dawley rats to observe the effects of tion and tubular reabsorption;93 consequently, the increase obesity on the expression of CYP2E1. Following 52 weeks in the renal clearance of lithium with no increase in of nutritional overfeeding, obese rats showed increased glomerular filtration66 supports decreased tubular reab- total CYP relative to control rats, unchanged CYP reduc- tase and cytochrome b5, increased CYP2E1, and unchangedCYP2C11 and CYP3A. A strong correlation was also shownbetween CYP2E1 activity and CYP2E1 protein immunoblot Obesity and Drug Pharmacodynamics
staining thereby reducing the significance of posttransla-tional modifications common to CYP2E1. The authors A final but equally important consideration when devel- further indicated that ketosis, often implicated as the oping a dosing strategy for an individual involves the mechanism by which CYP2E1 is increased, is likely not consideration of drug efficacy. Obese subjects were shown the primary mechanism of upregulation due to the fact that to have increased sensitivity to triazolam as measured by no significant increases were observed in CYP2B1 or CYP a sedation score upon administration of a second dose.46 reductase activities also commonly associated with ketosis.
The same dose of triazolam was used for both obese and Contrasting the genetic versus nutritional models, there nonobese individuals. Varin et al.41 showed that even appears to be a different mechanism of metabolic regula- though obese individuals were exposed to significantly tion influenced by either genetic expression or metabolic higher plasma concentrations of atracurium, no change was changes resulting in possible functional (i.e., enzymatic seen in the duration of neuromuscular blockade. The expression) and morphological (i.e., fatty infiltration in the authors attributed this change in sensitivity to a combina- liver associated with obesity) changes in obese rats. The tion of protein binding effects and desensitization of importance of these factors could easily manifest itself by acetycholine receptors. Desensitization of acetylcholine causing possible increases in toxicity following drug ad- receptors has been associated with chronic inactivity.74,75 ministration such as with the increased acetaminophen It is important to note that, with the plethora of probable genetic and nutritional changes associated with obesity, Chaudhary et al.80 provided evidence that glucuronida- changes in receptor expression or affinity for ligand could tion increased and sulfation pathways were unaffected in 4 / Journal of Pharmaceutical Sciences
the genetically obese Zucker rat. Using acetaminophen as clearance, volume of distribution, bioavailability, or phar- a substrate for glucuronidation and sulfation, the investi- macodynamics may affect the toxic potential of a drug.
gators observed no difference between urinary excretion Additionally, changes in excretion mechanisms can alter of acetaminophen sulfate and increased urinary excretion the toxicity of a compound by either increasing exposure of acetaminophen glucuronide in the genetically obese through decreased clearance or vice-versa. One study by Zucker rat when compared to normal-weight rats. No Georgiadis et al.91 observed the possible increases or change was observed for γ-glutamyl cysteine synthetase; decreases on the toxicity associated with the administration however, total glutathione and UDPGT increased in obese of a plethora of highly toxic chemotherapeutic agents to rats relative to normal-weight rats. This is an important obese versus lean subjects with small-cell lung cancer.
observation indicating that obese rats might have higher According to the study, no correlation could be established conjugation and detoxification pathways, but there is some between obesity and increased toxicity for patients receiv- discrepancy to this conclusion in that Barnett et al.81 ing cyclophosphamide, methotrexate, lomustine, etoposide, observed lower glutathione-S-transferase and total glu- and cisplatin. Perhaps the most important conclusion to tathione in genetically obese (ob/ob) mice indicating pos- be drawn from the information presented in this article is sibly higher susceptibility to toxicity in obese mice. The that each drug behaves differently. Predicting toxicity ob/ob mouse model associates noninsulin dependent dia- associated with obesity is very difficult if not impossible.
betes with obesity which likely manifests differential The best approach for pharmacotherapeutics in obese enzymatic expression mechanisms than nondiabetes-as- individuals is to use previous knowledge and be conserva- sociated obesity. Consequently, direct correlations between tive. Careful monitoring of the obese patient is necessary the two models is impossible, but the observation should when administering drugs with a small therapeutic index.
be made that there are several presently unidentifiedmechanisms involved in obesity that could possibly resultin the regulation and differential expression of many enzymes. An argument against the possibility that obese Using the parameters of volume of distribution and rats might have higher glutathione conjugation capacity clearance, a therapeutic dosing strategy can be developed is the fact that others have shown increased acetaminophen for a drug. Consequently, the effects of physiological toxicity in obese rats indicative of depeted glutathione.78 disorders on these parameters is important for accurate Sastre et al.82 used an overfed Wistar rat and Swiss mice pharmacotherapeutics. Regarding obesity, the volume of model to demonstrate that overfed mice had lower levels distribution has been shown to change in many situations.
of both reduced glutathione and oxidized glutathione than Generally, more lipophilic compounds are affected by chow fed mice. This study seemed to parallel the study by obesity to a greater extent than hydrophilic compounds.
Barnett et al.81 using a genetically obese mouse model in More lipophilic compounds are associated with increases that both models show a decreased propensity of obese mice in volume of distribution in obesity; however, there are for glutathione dependent conjugation and protection exceptions to this relationship. High LPC values did not against cellular insult. The contrast mentioned before correspond with markedly increased volumes of distribu- between obese Zucker rats and obese mice is also likely tion for digoxin,31 procainamide,32 and cyclosporine.15,26 influenced by species specific differences in obesity, another Consequently, prior knowledge of the effects of obesity on complication in the elucidation and parallel application of specific drugs is essential for accurate dosing strategies obesity associated mechanisms involved in pharmacoki- based upon volume of distribution; generalizations among similar groups of drugs does not always result in proper Contrasting the nutritional versus genetic models of physiologic responses between obese and lean individuals.
obesity, differences can be seen between genetic obesity and The clearance of a compound depends on the metabolic nutritional obesity for both Phase I and Phase II enzymatic activity of characteristic enzymes that may be affected by pathways. It should be noted that genetically induced obesity or diseases associated with obesity. Changes have obesity is targeted for a specific gene, but nutritional been noted in both humans and animals for various CYP obesity can have effects on multiple genes that in turn can isozymes using either direct measurements (in animals) effect the expression of many other genes. Consequently, or through the use of metabolic markers (in humans) such the pathways associated with nutritional obesity may be as antipyrine or erythromycin. In addition, obesity has been more variable and harder to elucidate. On the other hand, associated with increased glucuronidation with question- several current reviews83-86 cover the genetic causes and able effects on sulfation. Changes between obese and lean effects of obesity should the reader be interested in subjects have also been observed for antioxidant systems broadening his/her knowledge of the genetic influences of including glutathione and catalase. It is important to note obesity. Using genetic models, obesity has been linked to the variability in characterizing metabolic changes in deficiencies in leptin, a hormone shown to be secreted by obesity. Given the numerous possible genetic and environ- adipocytes87 that reduces body weight and food intake in mental influences, predicting changes in metabolic activity both obese and nonobese animals.88 Research into the can be difficult. Furthermore, there are possibilities that interactions of leptin with the body and the effects of similar concentrations of a drug at its site of action may obesity on leptin levels is generating volumes of new not elicit a similar response between obese and lean information into the molecular mechanisms of obesity and subjects, thereby making accurate therapeutic modifica- the possibilities that obesity might be under hormonal tions more difficult for obese individuals.
control. Several reviews89,90 evaluate the current under- Renal function, particularly glomerular filtration, has standing of leptin and its relationship with the body.
been shown to change with obesity. Increased glomerularfiltration in some studies has been contradicted by de- Pharmacotherapeutic Toxicity in Obesity
creases in glomerular filtration in other studies. Thesediscrepancies illustrate the possible ramifications of dif- The toxicity of substances can change with obesity. With ferent degrees of obesity, with morbidly obese individuals possible increases in metabolism such as with the CYP exhibiting different responses than moderately obese in- system, drugs can be converted to toxic metabolites at dividuals. The effects of obesity on the toxicology of specific higher rates; however, toxic drugs may also be converted compounds is questionable depending upon not only the to inactive metabolites at higher rates. Changes in the presence of enzymes that create toxic metabolites, but also Journal of Pharmaceutical Sciences / 5
depending upon the presence of enzymes that remove toxic 25. de Divitiis, O.; Fazio, S.; Petitto, M.; Maddalena, G.; Con- metabolites from the body. In conclusion, a safe therapeutic taldo, F.; Mancini, M. Obesity and cardiac function. Circula-
1981, 64, 477-482.
protocol for obese individuals should be based upon existing 26. Yee, G. C.; Lennon, T. P.; Gmur, D. J.; Cheney, C. L.; Oeser, therapeutic information as well as careful monitoring of D.; Deeg, H. J. Effect of obesity on CSA disposition. Trans- the patient during pharmacologic intervention.
plantation 1988, 45, 649-651.
27. Jung, D.; Mayersohn, M.; Perrier, D.; Calkins, J.; Saunders: R. Thiopental disposition in lean and obese patients under-
going surgery. Anesthesiology 1982, 56, 269-274.
References and Notes
28. Abernethy, D. R.; Greenblatt, D. J.; Divoll, M.; Shader, R. I.
Prolonged accumulation of diazepam in obesity. J Clin 1. Lew, E. A. Mortality and weight: Insured lives and the Pharmacol 1983, 23, 369-376.
Americal Cancer Society studies. Ann. Intern. Med. 1985,
29. Leo, A.; Hansch, C.; Elkin, D. Partition coefficients and their uses. Chem. Rev. 1971, 71, 525-616.
2. Pi-Sunyer, F. X. Medical hazards of obesity. Ann. Intern. Med. 30. Arendt, R. M.; Greenblatt, D. J.; Divoll, M.; Abernethy, D.
1993, 119, 655-660.
R.; Giles, H. G.; Sellers, E. M. Predicting in vivo benzodiaz- 3. Suissa, S.; Pollack, M.; Spitzer, W.; Margolese, R. Body size epine distribution based upon in vitro lipophilicity. Clin. and breast cancer prognosis: a statistical explanation of the Pharmacol. Ther. 1982, 31, 200-201.
discrepancies. Cancer Res. 1989, 49, 3113-3116.
31. Abernethy, D. R.; Greenblatt, D. J.; Smith, T. W. Digoxin 4. Seine, R. T.; Rosen, P. P.; Rhodes, P.; Lesser, M. L.; Kinne, disposition in obesity: clinical pharmacokinetic investigation.
D. W. Obesity at diagnosis of breast carcinoma influences Am. Heart J. 1981, 102, 740-744.
duration of disease-free survival. Ann. Intern. Med. 1992,
32. Christoff, P. B.; Conti, D. R.; Naylor, C.; Jusko, W. J.
Procainimide disposition in obesity. Drug Intell. Clin. Pharm. 5. Bastarrachea, J.; Hortobagyi, G. N.; Smith, T. L.; Kan, S.
1983, 23, 369-376.
W.; Buzdar, A. U. Obesity as an adverse prognostic factor 33. Ritchel, W. A.; Kaul, S. Prediction of apparent volumes of for patients receiving adjuvant chemotherapy for breast distribution in obesity. Methods Find Exp Clin Pharmacol cancer. Ann. Intern. Med. 1994, 119, 18-25.
1986, 8, 239-247.
6. Cheymol, G. Clinical pharmacokinetics of drugs in obesity: 34. Doherty, J. E.; Perkins, W. H.; Flanigan, W. J. The distribu- an update. Clin Pharmacokinet. 1993, 25, 103-114.
tion and concentration of tritiated digoxin in human tissues.
7. Blouin, R. A.; Chandler, M. H. H. Special pharmacokinetic Ann. Intern. Med. 1967, 66, 116-124.
considerations in the obese. Applied pharmacokinetics: prin- 35. Rohrbaugh, T. M.; Danish, M.; Ragni, M. C.; Yaffe, S. J. The ciples of therapeutic drug monitoring, 3rd ed.; Evans, W. E., effect of obesity on apparent volume of distribution of Schentag, J. J., Jusko, W. J., Ed.; Applied Therapeutics: theophylline. Pediatr. Pharmacol. 1982, 2, 75-83.
Vancouver, B.C., 1992; pp 11.3-11.20.
36. Gal, P.; Jusko, W. J.; Yurchak, A. M.; Franklin, B. A.
8. Cheymol, G. Drug pharmacokinetics in the obese. Fundam. Theophylline disposition in obesity. Clin. Pharmacol. Ther. Clin. Pharmacol. 1988, 2, 239-256.
1978, 23, 438-444.
9. Blouin, R. A.; Kolpek, J. H.; Mann, H. J. Influence of obesity 37. Rizzo, A.; Mirabella, A.; Bonanno, A. Effect of body weight on drug disposition. Clin. Pharmacy 1987, 6, 706-714.
on the volume of distribution of theophylline. Lung 1988, 166,
10. Abernethy, D. R.; Greenblatt, D. J. Drug disposition in obese humans: an update. Clin. Pharmacokinet. 1986, 11, 199-
38. Schwartz, S. N.; Pazin, G. J.; Lyon, J. A.; Ho, M.; Pasculle, A. W. A controlled investigation of the pharmacokinetics of 11. Abernethy, D. R.; Greenblatt, D. J.; Divoll, M.; Harmatz, J.
gentamicin and tobramycin in obese subjects. J Infect. Dis S.; Shader, R. I. Alterations in drug distribution and clear- 1978, 138, 499-505.
ance due to obesity. J Pharmacol. Exp. Ther. 1981, 217, 681-
39. Blouin, R. A.; Mann, H. J.; Griffen, W. O., Jr; Bauer, L. A.; Record, K. E. Tobramycin pharmacokinetics in morbidly 12. Corcoran, G. B.; Salazar, D. E.; Sorge, C. L. Pharmacokinetic obese patients. Clin. Pharmacol. Ther. 1979, 26, 508-512.
characteristics of the obese overfed rat model. Int. J. Obes. 40. Bauer, L. A.; Blouin, R. A.; Griffen, W. O., Jr; Bauer, L. A.; 1989, 13, 69-79.
Record, K. E. Amikacin pharmacokinetics in morbidly obese 13. Greenblatt, D. J.; Abernethy, D. R.; Locniskar, A.; Harmatz, patients. Am. J. Hosp. Pharm. 1980, 3, 519-522.
J. S.; Limjuco, R. A.; Shader, R. I. Effect of age, gender, and 41. Varin, F.; Ducharme, J.; Theoret, Y.; Besner, J. G.; Bevan, obesity on midazolam kinetics. Anesthesiology 1984, 61, 27-
D. R.; Donati, F. Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium.
14. Bowman, S. L.; Hudson, S. A.; Simpson, G.; Munro, J. F.; Clin. Pharmacol. Ther. 1990, 48, 18-25.
Clements, J. A. A comparison of the pharmacokinetics of 42. Le Jeunne, C. L.; Poirier, J. M.; Cheymol, G.; Ertzbischoff, propanolol in obese and normal volunteers. Br. J. Clin. O.; Engel, F.; Hugues, F. C. Pharmacokinetics of intravenous Pharmacol. 1986, 21, 529-532.
bisoprolol in obese and nonobese volunteers. Eur. J. Clin. 15. Flechner, S. M.; Kolbeinsson, M. E.; Tam, J.; Lum, B. The Pharmacol. 1991, 41, 171-174.
impact of body weight on cyclosporine pharmacokinetics in 43. Cheymol, G.; Woestenborghs, R.; Snoeck, E.; Ianucci, R.; Le renal transplant recipients. Transplantation 1989, 47, 806-
Moing, J. P.; Naditch, L.; Levron, J. C.; Poirier, J. M.
Pharmacokinetic study and cardiovascular monitoring of 16. Cheymol, G.; Weissenburger, J.; Poirier, J. M.; Gellee, C. The nebivolol in normal and obese subjects. Eur. J. Clin. Phar- pharmacokinetics of dexfenfluramine in obese and nonobese macol. 1997, 51, 493-498.
subjects. Br. J. Clin. Pharmacol. 1995, 39, 684-687.
44. Abernethy, D. R.; Greenblatt, D. J. Phenytoin disposition in 17. Rowland, M.; Tozer, T. N. Clinical Pharmacokinetics: Con- obesity. Arch. Neurol. 1985, 42, 468-471.
cepts and Applications, 2nd ed.; Lea and Febiger: Philadel- 45. Cheymol, G. Comparative pharmacokinetics of intravenous propanolol in obese and normal volunteers. J. Clin. Phar- 18. Benedek, I. H.; Fiske, W. D., III; Griffen, W. O.; Bell, R. M.; macol. 1987, 27, 874-879.
Blouin, R. A.; McNamara, P. J. Serum alpha1-acid glycopro- 46. Derry, C. L.; Kroboth, P. D.; Pittenger, A. L.; Kroboth, F. J.; tein and the binding of drugs in obesity. Br. J. Clin. Corey, S. E.; Smith, R. B. Pharmacokinetics and pharmaco- Pharmacol. 1983, 16, 751-754.
dynamics of triazolam after two intermittent doses in obese 19. Benedek, I. H.; Blouin, R. A.; McNamara, P. J. Serum protein and normal-weight men. J. Clin. Psychopharmacol. 1995, 15,
binding and the role of increased alpha1-acid glycoprotein in moderately obese male subjects. Br. J. Clin. Pharmacol. 47. Abernethy, D. R.; Schwartz, J. B. Verapamil pharmacody- 1984, 18, 941-946.
namics and disposition in obese hypertensives J. Cardiovasc. 20. Kjellberg, J.; Reizenstein, P. Body composition in obesity.
Pharmacol. 1988, 11, 209-215.
Acta Med. Scand. 1970, 188, 161-169.
48. Abernethy, D. R.; Greenblatt, D. J.; Divoll, M.; Shader, R. I.
21. Naeye, R. L.; Rode, P. The sizes and numbers of cells in Prolongation of drug half-life due to obesity: studies of visceral organs in human obesity. Am. J. Clin. Pathol. 1970,
desmethyldiazepam (clorazepate). J. Pharm. Sci. 1982, 7,
22. Smith, H. L. The relation of the weight of the heart to the 49. Sherlock, S. Diseases of the liver biliary system, 7th ed.; weight of the body and of the weight of the heart to age. Am. Blackwell Scientific Publications: Boston, 1985, p 384.
Heart J. 1928, 4, 79-93.
50. Vaughan, R. W. Definitions and risks of obesity. In Anes- 23. Alexander, J. K.; Dennis, E. W.; Smith, W. G.; Amad, K. H.; thesia and the Obese Patient; Brown, B. R., Ed.; 1982; F. A.
Duncan, W. C.; Austin, R. C. Blood volume, cardiac output, and disposition of systemic blood flow in extreme obesity.
51. Caraco, Y.; Zylber-Katz, E.; Berry, E. M.; Levy, M. Antipyrine Cardiovasc. Res. Cent. Bull. 1962-1963, 1, 39-44.
disposition in obesity: evidence for negligible effect of obesity 24. Alexander, J. K. Obesity and cardiac performance. Am. J. on hepatic oxidative metabolism. Eur. J. Clin. Pharmacol. Cardiol. 1964, 14, 860-865.
1995, 47, 525-530.
6 / Journal of Pharmaceutical Sciences
52. Hunt, C. M.; Watkins, P. B.; Saenger, P.; Stave, G. M.; 75. Gronert, G. A. Disuse atrophy with resistance to pancuro- Barlascini, N.; Watlington, C. O.; Wright, J. T.; Guzelian, P.
nium. Anesthesiology 1981, 55, 547-549.
S. Heterogeneity of CYP3A isoforms metabolizing erythro- 76. Irizar, A.; Barnett, C. R.; Flatt, P. R.; Ioannides, C. Defective mycin and cortisol. Clin. Pharmacol. Ther. 1992, 51, 18-23.
expression of cytochrome P450 proteins in the liver of the 53. Hunt, C. M.; Westerkam, W. R.; Stave, G. M.; Wilson, J. A.
genetically obese zucker rat. Eur. J. Pharmacol. Environ. P. Hepatic cytochrome P-4503A (CYP3A) activity in the Toxicol. Pharmacol. Sect. 1995, 293, 385-393.
elderly. Mech. Aging Dev. 1992, 64, 189-199.
77. Raucy, J. L.; Lasker, J. M.; Kraner, J. C.; Salazar, D. E.; 54. Abernethy, D. R.; Greenblatt, D. J.; Divoll, M.; Shader, R. I.
Lieber, C. S.; Corcoran, G. B. Induction of cytochrome Enhanced glucuronide conjugation of drugs in obesity: stud- P450IIE1 in the obese overfed rat. Mol. Pharmacol. 1991,
ies of lorazepam, oxazepam, and acetaminophen. J. Lab. Clin. Med. 1983, 101, 873-880.
78. Corcoran, G. B.; Wong, B. K. Obesity as a risk factor in drug- 55. Abernethy, D. R.; Divoll, M.; Greenblatt, D. J.; Ameer, B.
induced organ injury: increased liver and kidney damage Obesity, sex, and acetaminophen disposition. Clin. Pharma- by acetaminophen in the obese overfed rat. J. Pharmacol. col. Ther. 1982, 31, 783-790.
Exp. Ther. 1987, 241, 921-927.
56. Cummins, A. J.; King, K. L.; Martin, B. K. A kinetic study 79. Salazar, D. E.; Sorge, C. L.; Corcoran, G. B. Obesity as a risk of drug elimination: the excretion of paracetamol and its factor for drug-induced organ injury VI: increased hepatic metabolites in man. Br. J. Pharm. Chem. 1967, 29, 150-
P450 concentration and microsomal ethanol oxidizing activity in the obese overfed rat. Biochem. Biophys. Res. Commun. 57. Greenblatt, D. J.; Abernethy, D. R.; Boxenbaum, H. G.; 1988, 157, 315-320.
Matlis, R.; Ochs, H. R.; Harmatz, J. S.; Shader, R. I. Influence 80. Chaudhary, I. P.; Tuntaterdtum, S.; McNamara, P. J.; of age, gender, and obesity on salicylate kinetics following Robertson, L. W.; Blouin, R. A. Effect of genetic obesity and doses of aspirin. Arthritis Rheum 1986, 29, 971-980.
phenobarbitol treatment on the hepatic conjugation path- 58. Rafecas, I.; Fernandez-Lopez, J. A.; Salinas, I.; Formiguera, ways. J. Pharmacol. Exp. Ther. 1993, 265, 1333-1338.
X.; Remesar, X.; Foz, M.; Alemany, M. Insulin degradation 81. Barnett, C. R.; Abbott, R. A.; Bailey, C. J.; Flatt, P. R.; by adipose tissue is increased in human obesity. J. Clin. Ioannides, C. Cytochrome P450-dependent mixed-function Endocr. Metab. 1995, 80, 693-695.
oxidase and glutathione-S-transferase activities in spontane- 59. Milsap, R. L.; Plaisance, K. I.; Jusko, W. J. Prednisolone ous obesity diabetes. Biochem. Pharmacol. 1992, 43, 1868-
disposition in obese men. Clin. Pharmacol. Ther. 1984, 36,
82. Sastre, J.; Pallardo, F. V.; Llopis, J.; Furukawa, T.; Vina, J.
60. Caraco, Y.; Zylber-Katz, E.; Berry, E. M.; Levy, M. Significant R.; Vina, J. Glutathione depletion by hyperphagia-induced weight reduction in obese subjects enhances carbamazepine obesity. Life Sci. 1989, 45, 183-187.
elimination. Clin. Pharmacol. Ther. 1992, 51, 501-506.
83. Naggert, J.; Harris, T.; North, M. The genetics of obesity.
61. Caraco, Y.; Zylber-Katz, E.; Berry, E. M.; Levy, M. Carbam- Curr. Opin. Genet. Dev. 1997, 7, 398-404.
azepine pharmacokinetics in obese and lean subjects. Ann. 84. Pi-Sunyer, F. X. Energy balance: role of genetics and activity.
Pharmacother. 1995, 29, 843-847.
Ann. N.Y. Acad. Sci. 1997, 819, 29-36.
62. Davis, R. L.; Quenzer, R. W.; Bozigian, H. P.; Warner, C. W.
85. Saladin, R.; Staels, B.; Auwerx, J.; Briggs, M. Regulation of Pharmacokinetics of ranitidine in morbidly obese women.
ob gene expression in rodents and humans. Horm. Metab. DICP Ann. Pharmacother. 1990, 24, 1040-1043.
Res. 1996, 28, 638-41.
63. Stokholm, K. H.; Brochner-Mortenson, J.; Hoilund-Carlsen, 86. Roberts, S. B.; Greenberg, A. S. The new obesity genes. Nutr. P. F. Glomerular filtration rate and adrenocortical function Rev. 1996, 54, 41-49.
in obese women. Int. J. Obes. 1980, 4, 57-63.
87. Zhang, Y.; Proneca, R.; Maffei, M.; Barone, M.; Leopold, L.; 64. Dionne, R. E.; Bauer, L. A.; Gibson, G. A.; Griffen, W. O., Jr; Friedman, J. M. Positional cloning of the mouse obese gene Blouin, R. A. Estimating creatinine clearance in morbidly and its human analogue. Nature 1994, 372, 425-432.
obese patients. Am. J. Hosp. Pharm. 1981, 38, 841-844.
88. Campfield, L. A.; Smith, F. J.; Burn, P. The QB protein 65. Ducharme, M. P.; Slaughter, R. L.; Edwards, D. J. Vanco- (leptin) pathway: a link between adipose tissue mass and mycin pharmacokinetics in a patient population: effect of central neural networks. Horm. Metab. Res. 1996, 28, 619-
age, gender, and body weight. Ther Drug Monit 1994, 16,
89. Considine, R. V.; Caro, J. F. Leptin: genes, concepts, and 66. Reiss, R. A.; Haas, C. E.; Karki, S. D.; Gumbiner, B.; Welle, clinical perspective. Horm. Res. 1996, 46, 249-256.
S. L.; Carson, S. W. Lithium pharmacokinetics in the obese.
90. Caro, J. F.; Sinha, M. K.; Kolaczynski, J. W.; Zhang, P. L.; Clin. Pharmacol. Ther. 1994, 55, 392-398.
Considine, R. V. Leptin: the tale of an obesity gene. Diabetes 67. Allard, S.; Kinzig, M.; Boivin, G.; Sorgel, F.; LeBel, M.
1996, 45, 1455-1462.
Intravenous ciprofloxacin disposition in obesity. Clin. Phar- 91. Georgiadis, M. S.; Steinberg, S. M.; Hankins, D. C.; Johnson, macol. Ther. 1993, 54, 368-373.
B. E. Obesity and therapy related toxicity in patients treated 68. Bauer, L. A.; Edwards, W. A.; Dellinger, E. P.; Simonowitz, for small-cell lung cancer. J. Nat. Cancer Inst. 1995, 87, 361-
D. A. Influence of weight on aminoglycoside pharmacokinet- ics in normal weight and morbidly obese patients. Eur. J. 92. Vance-Bryan, K.; Guay, D. R.; Rotschafer, J. C. Clinical Clin. Pharmacol. 1983, 24, 643-647.
pharmacokinetics of ciprofloxacin. Clin. Pharmacokinet. 69. Korsager, S. Administration of gentamicin to obese patients.
1990, 19, 434-461.
Int. J. Clin. Pharmacol. Ther. Toxicol. 1980, 18, 549-553.
93. DePaulo, J. R.; Correa, E. I.; Sapir, D. G. Renal toxicity of 70. Sketris, L.; Lesar, T.; Zaske, D. E.; Cipolle, R. J. Effect of lithium and its implications. Johns Hopkins Med. J. 1981,
obesity on gentamicin pharmacokinetics. J. Clin. Pharmacol. 1981, 21, 228-293.
94. O′Shea, D.; Davis, S. N.; Kim, R. B.; Wilkinson, G. R. Effect 71. Blouin, R. A.; Bauer, L. A.; Miller, D. D.; Record, K. E.; of fasting and obesity in humans on the 6-hydroxylation of Griffen, W. O., Jr. Vancomycin pharmacokinetics in normal chlorzoxazone: a putative probe of CYP2E1 activity. Clin. and morbidly obese subjects. Antimocrob. Agents Chemother. Pharmacol. Ther. 1994, 56, 359-367.
1982, 21, 575-580.
95. Drayer, D. E.; Romankiewicz, J.; Lorenzo, B.; Reidenberg, 72. Abernethy, D. R.; Greenblatt, D. J.; Matlis, R.; Gugler, R.
M. M. Age and renal clearance of cimetidine. Clin. Pharma- Cimetidine disposition in obesity. Am. J. Gastroenterol. 1984,
col. Ther. 1982, 31, 45-50.
73. Bauer, L. A.; Wareing-Tran, C.; Edwards, W. A.; Raisys, V.; Acknowledgments
Ferreri, L.; Jack, R.; Dellinger, E. P. Cimetidine clearance
in the obese. Clin. Pharmacol. Ther. 1985, 37, 425-530.
G.W. was supported, in part, by an NIEHS Training Grant 74. Waud, B. E.; Waud, D. R. Turboaurarine sensitivity of the diaphragm after limb immobilizaiton. Anesth. Analg. 1986,
65, 493-495.
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