Journal of Pharmaceutical Investigation (2013) 43:161–169 DOI 10.1007/s40005-013-0073-4
REVIEW
Obesity-related physiological changes and their pharmacokinetic consequences Sung-Joon Cho • In-Soo Yoon • Dae-Duk Kim
Received: 13 March 2013 / Accepted: 22 April 2013 / Published online: 1 May 2013 Ó The Korean Society of Pharmaceutical Sciences and Technology 2013
Abstract The prevalence of obesity has soared in recent decades, and now is considered as a worldwide problem, with significant health and medical implications. Obesity is often linked to several co-morbidities including diabetes, cardiovascular diseases, and cancers, and a number of drugs are available for the treatment of these diseases. Moreover, obesity can affect various physiological factors including plasma proteins, drug metabolizing enzymes, drug transporters, and blood flow, thereby altering drug absorption, distribution, metabolism, and excretion (ADME). Therefore, information regarding obesity-related physiological changes and their pharmacokinetic consequences is crucial for understanding pharmacokinetics and optimizing drug therapy in obese population. Herein, this article reviews the effects of obesity on physiological factors determining drug ADME and their pharmacokinetic consequences. In addition, a brief summary on animal models of obesity is presented. Keywords
Obesity Pharmacokinetics Animal models
Abbreviations CL Total body clearance CLH Hepatic clearance CLR Renal clearance S.-J. Cho D.-D. Kim (&) College of Pharmacy and Research Institute of Pharmlaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea e-mail:
[email protected] I.-S. Yoon College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea
Vd Tmax F fu EH NASH NAFLH CPR
Volume of distribution Time to reach a peak plasma concentration Extent of absolute oral bioavailability Free fraction of a drug in plasma Hepatic extraction ratio Non-alcoholic steatohepatitis Non-alcoholic fatty liver hepatitis NADPH-cytochrome P450 reductase
Introduction Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have adverse effects on health, leading to reduced life expectancy and/or increased health problems. People are diagnosed as obese when their body mass index (BMI), a measurement obtained by dividing a person’s weight in kilogram by the square of the person’s height in meter, exceeds 30 kg/m2. Obesity can be induced mainly by a combination of excessive food energy intake, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by endocrine disorders, genes, and medications. The prevalence of obesity has soared in recent decades, and now is considered as a worldwide problem, with significant health and medical implications. It has been reported that about 58 % of the world’s population will be either overweight or obese by 2030 (Kelly et al. 2008). Obesity is often linked to several co-morbidities including diabetes, cardiovascular diseases, and cancers (Morrish et al. 2011). Thus, drug therapy in obese population may be highly prevalent. For many drugs including anti-diabetic, anti-hypertensive, and anti-cancer agents, altered pharmacokinetics and dosage regimen adjustments in obese population have been reported (Jain et al. 2011).
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Those pharmacokinetic alterations can be attributed mainly to obesity-related changes in physiological factors such as plasma proteins, drug metabolizing enzymes, drug transporters, and blood flow, which are known to determine drug absorption, distribution, metabolism, and excretion (ADME) (Jain et al. 2011). Therefore, a comprehensive review on obesity-related physiological changes and their pharmacokinetic consequences is required to facilitate the understanding of pharmacokinetics and optimization of drug therapy in obese population. Herein, we summarize current knowledge on the effects of obesity on physiological factors determining drug ADME and their pharmacokinetic consequences. In addition, a brief overview on animal models of obesity is presented.
Effects of obesity on drug absorption In obese people, increased blood flow to perfuse the gut may enhance the rate and extent of oral drug absorption (Wise´n and Hellstro¨m 1995; Adams and Murphy 2000). Moreover, accelerated gastric emptying may lead to a decrease in the time to reach peak plasma concentration (Tmax) (Wright et al. 1983; Zahorska-Markiewicz et al. 1986). However, there are few human studies reporting the change in oral drug absorption in obese population. It has been reported that oral bioavailability of midazolam, propranolol, and dexfenfluramine is not significantly changed in obesity patients compared to that in those without obesity (Greenblatt et al. 1984; Bowman et al. 2012). The absorption of drugs administered transdermally, subcutaneously, and intramuscularly depends on blood flow to perfuse the skin, subcutaneous fat, and muscle, respectively. Although cardiac output is increased in obese population, the blood flow rate per gram of fat tissue in morbidly obese is significantly lower than that in normal subjects, which may affect the rate and/or extent of absorption of drugs administered subcutaneously (Lesser and Deutsch 1967). The absorption rate of enoxaparin, low-molecular-weight heparin, after subcutaneous administration was decreased, and the median time to reach maximum activity level was increased by 1 h in obese volunteers than those without obesity (Sanderink et al. 2002).
Effects of obesity on drug distribution The volume of distribution (Vd) of a drug depends on various factors including physicochemical property of a drug, tissue size, tissue permeability, plasma protein binding, and the affinity of a drug for tissue components (Bryson 1983). Obesity is associated with changes in physiological factors including protein binding constituents, adipose tissue mass,
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lean body mass, organ mass, cardiac output, and splanchnic blood flow, which can potentially lead to change in the Vd (Blouin and Warren 1999). Changes in the Vd are generally known to be highly dependent on lipophilicity of a drug. As body weight increases, fat tissue mass increases more rapidly than lean body mass. Lipophilic and hydrophilic drugs tend to be more distributed into fat tissue and lean body tissue, respectively. Thus, the magnitude of change in the Vd by obesity tends to be larger in lipophilic drugs (Blouin and Warren 1999), except cyclosporine. It has been reported to have comparable Vd between obese and normal subjects, although cyclosporine is a highly lipophilic compound with a relatively large Vd (Flechner et al. 1989; Yee et al. 1988). Because of differences in tissue massincreasing profiles and drug distribution ratios between fat and lean tissue, proper weight descriptors as a normalizer with respect to the Vd should be selected for dosage adjustment in obese patients. For example, weight descriptors of anesthetics are shown in Table 1 (Leykin et al. 2011). Plasma protein concentration and drug-protein affinity can be also affected by obesity. Plasma free fraction (fu) of drugs primarily bound to albumin (e.g. thiopental and phenytoin) is not significantly changed in obese population (Jung et al. 1982; Benedek et al. 2012b), while the fu of drugs primarily bound to a1-acid glycoprotein (AAG) can be affected by obesity (Blouin and Warren 1999). Significant increase in AAG concentrations and concomitant decrease in the fu of propranolol have been observed in obese patients (Benedek et al. 2012a). However, there were no significant changes in the fu of triazolam and verapamil, probably due to changes in drug-protein affinity (Blouin and Warren 1999).
Effects of obesity on hepatic drug metabolism Liver plays a major role in drug metabolism. Obese individuals often have fatty liver or non alcoholic fatty liver
Table 1 Weight descriptors for dose adjustment of anesthetics in obese patients Anesthetics
Weight descriptors
Thiopental
LBW
Propofol
TBW
Succinylcholine
TBW
Rocuronium
IBW
Cis-atracurium
IBW
Vencuronium
IBW
Fentanyl
LBW
This table was modified from the reference (Leykin et al. 2011) LBW lean body weight, TBW total body weight, IBW ideal body weight
Obesity-related physiological changes
hepatitis (NAFLH), which leads to considerable changes in liver function. Fatty infiltration in the liver is known to be a common characteristic of obesity. Fatty infiltration can cause mild alcoholic hepatitis in moderately obese individuals but serious liver damage in morbidly obese individuals. These factors could have a significant impact on the expression and activity of drug metabolizing enzymes, which then leads to changes in pharmacokinetics of drugs. Phase 1 metabolism Phase 1 enzymes catalyze the modification of functional groups of a substrate (i.e. oxidation, reduction and hydrolysis) and the majority of these enzymes are CYPs. CYPs are predominantly located in the endoplasmic reticulum of hepatocytes and oxidize organic substances with the presence of NADPH, NADP reduction systems (Brill et al. 2012). CYPs-mediated metabolism is responsible for metabolism of *75 % of marketed drugs (Guengerich 2007). CYP3A4 accounts for *50 % of phase 1 metabolism (Evans and Relling 1999). Brill et al. investigated pharmacokinetic data of ten CYP3A4 substrates; alfentanyl, midazolam, triazolam, alprazolam, ciclosporin, carbamazepine, docetaxel, taranabant, trazodone, and N-demethylerythromycin. Among them, taranabant (37 % decrease in CL/F), carbamazepine (14 % decrease in CL), midazolam (11 % decrease in CL), triazolam (36 % decrease in CL),
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alprazolam (25 % decrease in CL), ciclosporin (11 % decrease in CL) and alfentanil (45 % decrease in CL) exhibited a significantly lower total body clearance (CL) in obese patients (Brill et al. 2012). CYP2E1 is closely related to obesity, because it is involved in the lipid oxidation metabolism and may play a major role in inducing non alcoholic fatty liver disease (Gomez-Lechon et al. 2009). Although CYP2E1-mediated metabolism accounts for only about 5 % of phase 1 drug metabolism, four previous studies were performed to show the effects of obesity on CYP2E1-mediated metabolism of four probe substrates (chlorzoxazone, enflurane, sevoflurane, and halothane). In those studies, significant increases in CL were observed, suggesting the induction of CYP2E1 activity in obese patients. Fatty infiltration is known to be the underlying mechanism of the CYP2E1 induction (Emery et al. 2003). It has also been reported that an increase of CYP 2E1-mediated clearance is closely related to body weight and the degree of liver steatosis (Brill et al. 2012). CYP2D6-mediated metabolism accounts for about 10–15 % of phase 1 drug metabolism in humans (Evans and Relling 1999). The CYP2D6 is well known as its genetic polymorphism (May 1994). CYP2D6-mediated metabolism tends to increase in obese population. CYP1A2 and 2C9-mediated metabolism also tend to increase in obese population. The CYP2C19 is also well known as its genetic polymorphism (Brill et al. 2012). The CLs of
Fig. 1 Influence of fatty acids (FA) influx on the activity and expression of nuclear receptors (NRs) and membrane composition of microsomes. The activity of various NRs can be directly or indirectly affected by influx of FA into the liver, oxysterols and bile acids (solidline arrows). Moreover, FA can function as ligands (agonists or antagonists) of constitutive androstane receptor (CAR), farnesoid X recepetor (FXR) and liver X receptor (LXR) (dashed-lined arrow). Membrane composition of microsomes can be changed by FA (hollowed-arrow)
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diazepam and methyl diazepam, probe substrates of CYP2C19, were significantly increased and not changed in obese population (Abernethy et al. 1981a, 1982b). However, their CLs normalized with respect to body weight slightly decreased in obese individuals. The activities of phase 1 enzymes other than CYPs were also changed in obese people. For example, xanthine oxidase-mediated metabolism of mercaptopurine was significantly increased in obese children (Chiney et al. 2011). Several studies were conducted to investigate the mechanism of changes in the activity of CYPs. Plasma fatty acid can interact with various nuclear receptors(NR) and transcription factors (Jump et al. 2005), which can lead to the change in the expression of CYPs. Moreover, elevated levels of fatty acid can affect membrane compositions of endoplasmic reticulum or microsomes. The altered lipid compositions of microsomal membranes can possibly affect the interplay between CYPs and NADPH-cytochrome P450 reductase (CPR) and/or cytochrome b5 through changing the catalytic capacity of CYPs system (Fig. 1) (Leclercq et al. 1998; Su et al. 1999). Phase 2 metabolism Phase 2 metabolism includes several conjugation reactions such as glucuronidation, acetylation, methylation, and sulfation. Among various phase 2 enzymes, uridine disphosphate glucuronosyltransferase (UGT) enzymes represent about 50 % of phase 2 metabolism, which are considered to be the most important phase 2 enzyme (Evans and Relling 1999). The human UGT superfamily consists of two families (UGT1 and UGT2) and three subfamilies (UGT1A, 2A, 2B). Many of UGT enzymes are expressed not only in the liver but also in extrahepatic tissues such as the gastrointestinal tract, adipose, and kidney in which the extent of glucuronidation could be considerable (Kiang et al. 2005). Brill et al. summarized several studies on metabolism of four UGT substrates (paracetamol, garenoxacin, oxazepam, and lorazepam) in obesity. All studies commonly reported significantly increased CLs in obese as compared to non-obese subjects (Abernethy et al. 1982a). However, the CL values normalized with respect to body weight were equal or slightly lower for obese compared to non-obese subjects, except oxazepam which showed a significant increase in body weight-normalized CL (Brill et al. 2012). For acetylation and glutathione conjugation, the CL of procainamide, substrate of N-acetyltransferase, slightly increased in obese compared to non-obese adults, but this increase was not statistically significant (Brill et al. 2012). The oral CL of busulfan, substrate of glutathione S-transferase, slightly increased in obese compared to non-obese patients. However, the CL values normalized with respect to body weight
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were significantly lower in obese versus non-obese subjects (Gibbs et al. 1999). Hepatic blood flow The CL of a drug with high hepatic extraction ratio (EH) depends on hepatic blood flow only, rather than intrinsic metabolic clearance or protein binding. However, the impact of obesity on liver blood flow remains controversial and unclear. Farrell et al. reported that non-alcoholic steato hepatitis (NASH) increases fat disposition in the liver, leading to sinusoidal narrowing and reduction in hepatic blood flow (Farrell et al. 2008). In contrast, however, Casati et al. reported that hepatic blood flow is not necessarily reduced in obese subjects due to increased blood volume and cardiac output (Casati and Putzu 2005). Propofol is extensively metabolized by various UGTs, and its CL is mainly limited by hepatic blood flow (Kiang et al. 2005; Al-Jahdari et al. 2006). Van Krelingen et al. and Cortinez et al. reported that total body weight as a covariate for CL improved the predictive performances of population pharmacokinetic models (van Kralingen et al. 2011; Cortinez et al. 2010). The CL of propranolol, a drug with high EH, was changed (Cheymol et al. 1997; Bowman et al. 2012; Wo´jcicki et al. 2003), and the CL of labetalol and sulfentanil increased in obese patients (Cheymol et al. 1997). However, the CL of lidocaine, a drug with high EH, was not significantly changed. Brill et al. reported that the CLs of only a few drugs with high hepatic extraction ratio were changed in obese compared to non-obese subjects and that the CL normalized with respect to body weight significantly decreased (Brill et al. 2012).
Effects of obesity on renal drug excretion Renal excretion process consists of glomerular filtration, tubular secretion and tubular reabsoprtion. Obese patients were reported to have 62 % higher mean estimated glomerular filtration rate (eGFR) (Pai 2010). Obesity may be related to end stage renal disease, because focal glomerular sclerosis and/or diabetic nephropathy have been observed in morbidly obese patients (Kasiske and Crosson 1986). Therefore, obesity is believed to affect kidney function, which may lead to changes in renal drug excretion. Glomerular filtration Various studies have been conducted with drugs which are eliminated mainly by glomerular filtration. Bauer et al. reported that the CL of vancomycin in morbidly obese patients increased with total body weight, compared with non-obese patients (Bauer et al. 1998). The CL of
Obesity-related physiological changes
daptomycin was reported to increase in a higher mean total body weight (126 kg), although no significant change in CL was observed in obese patients with a mean total body weight of 114 kg (Pai et al. 2007). Carboplatin is eliminated mainly by glomerular filtration and partly by tubular secretion (Harland et al. 1984). The CL of carboplatin was reported to have positive correlations with both total body weight and ideal body weight (Ekhart et al. 2009; Schmitt et al. 2009). The CLs of low-molecular-weight heparins (enoxaparin, tinzaparin, and dalteparin) increased in obese subjects compared with non-obese patients (Barras et al. 2009; Yee and Duffull 2000; Barrett et al. 2001). Tubular secretion and reabsorption Approximately 50 % of procainamide dose is excreted via glomerular filtration and active tubular secretion. Renal clearance (CLR) of procainamide was reported to increase in obese patients due to elevated tubular secretion, while no significant change in 24-h creatinine clearance indicating no difference in glomerular filtration was observed between obese and non-obese patients (Brill et al. 2012). The CL values of cisplatin and ciprofloxacin, which are eliminated mainly by tubular secretion, increased in obese subjects (Drusano 1987; Allard et al. 1993; Daley-Yates and Mcbrien 1982). The CL values of topotecan and digoxin tended to increase in obese patients, probably due to the increased tubular secretion (Abernethy et al. 1981b; Sparreboom et al. 2007). However, the CL values normalized with respect to body weight were equal or slightly lower in obese compared with non-obese patients (Brill et al. 2012). Tubular reabsorption of lithium was reported to be decreased, while the CL of lithium was significantly elevated in obese patients, and glomerular filtration did not differ between obese and non-obese patients (Reiss et al. 1994). Proximal tubular reabsorption of sodium in obese patients is reported to be increased due to glomerular hyperfiltration (Chagnac et al. 2008). Thus, the effect of obesity on tubular reabsorption is not clear and controversial due to insufficient data.
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been reported that the mRNA and protein expressions of ABCC1, ABCC4-5, and ABCG2 tend to increase with NAFLD progression (Hardwick et al. 2011). In the study, molecular mass shift of ABCC2 from 200 to 180 kDa was also observed, which may be attributed to the loss of glycosylaton and internalization of protein. Altered expression and function in various transporters was observed in db/db mouse which is known to be an animal model of type 2 diabetes and obesity (Lam et al. 2010). More et al. compared the expressions of hepatic and renal transporters in ob/ob mice, db/db mice, and dietinduced (DIO) mice. They reported that these three animal models showed altered expression of transporters in liver and kidney, and DIO mice exhibited the induction of efflux transporter expression in liver (More and Slitt 2011). The protein expression of hepatic Mrp3 in methionine-choline deficient (MCD) model with NAFLH was reported to increase. This result is consistent with increased elimination of APAP–GLUC in same animal model (Lickteig et al. 2007). A previous study using rodent models of obesity reported significant decreases in the expression of Table 2 Physiological changes in obesity and their pharmacokinetic consequences Physiological changes
Pharmacokinetic consequences
Accelerated gastric emptying Rate and extent of oral drug Blood flow to perfuse the gut absorption (:) (:) Lean body mass (:)
Vd
Adipose mass (:)
Hydrophilic drugs (moderately :)
Organ sizes (:)
Lipophilic drugs (highly :)
Cardiac output (:) AAG (:)
fu
Plasma lipids (:)
Basic drugs (;)
Free fatty acids (:)
Acidic drugs (:)
Splanchnic blood flow (:) Number of hepatocytes (:) Fatty infiltration to liver (:)
CLH Altered hepatic metabolism and biliary excretion
Cholestasis (:) Periportal fibrosis and infiltration (:) Canalicular transporters (;)
Effects of obesity on drug transporters
Phase I enzymes (:), (;), or ($)
It has been widely reported that drug transporters play a significant role in drug ADME. Several studies showed that obesity could change the expression and activity of drug transporters, which may lead to the change of pharmacokinetics of substrate drugs. The increased expression of multiple efflux transporters as well as altered cellular localization of ABCC2 was observed in the liver of patients with nonalcoholic fatty liver diseases (NAFLD). It has
Sulfation and glucuronidation (:) Kidney size (:) Glomerular surface area and filtration (:)
CLR Filtration and tubular secretion (:) Altered tubular reabsorption
Renal blood flow (:) Urine pH (:) This table was modified from the reference (Edelman et al. 2010)
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Table 3 Alterations of hepatic CYPs in diet-induced animal models of obesity Experimental model
Total CYP content CYP enzyme Activity
Rats (MCD diet)
;
CYP 2E1
Decrease (testosterone 7a-hydroxylation)
CYP2C11
Decrease (testosterone 2a- and 16a-hydroxylation)
CYP3A2
Decrease (testosterone 6b-hydroxylation)
Protein mRNA
CYP2E1
Increase (N,N-dimethylnitrosamine N-demethylation) :
Rats (high-carbohydrate fat free) ;
CYP2E1
Decrease (chlorzoxazone hydroxylation)
CYP3A1
Decrease (erythromycin N-demethylation)
;
CYP1A2
$
CYP2E1
:
CYP3A
;
CYP4A
:
Mice (high-fat diet)
:
; ;
This table was modified from the reference (Gomez-Lechon et al. 2009)
canalicular transporters such as the bile salt export pump and organic anion transporter 1, which can lead to decrease in biliary excretion of drugs (Geier et al. 2005). Obesity-related physiological changes which determine the ADME of drugs and their pharmacokinetic consequences are summarized in Table 2 (Edelman et al. 2010).
Animal models of obesity Diverse animal models of obesity have been developed since studies using proper animal disease model are indispensable in understanding disease mechanisms and other issues including pharmacokinetics in human. Animal models of obesity can be divided broadly in three categories. Gene-modified models (monogenic models), dietinduced models (polygenic models), and surgical or chemical models (Speakman et al. 2007). Each category has various subordinate models. However, due to the advance of genetic models, use of surgical or chemical models of obesity has been diminishing. Here, we explain animal models of obesity which have been widely used in pharmacokinetics-related research area.
deficiency has also been observed in rare cases of human obesity (O’Rahilly 2009). db/db mouse (Lepdb/Lepdb mouse, the diabetic mouse) and Zucker rat db/db mouse is a genetically modified mouse which lacks leptin receptor. This animal model exhibits similar phenotype to the ob/ob mouse. The major difference between the two models is that the db/db mouse has an abnormal leptin receptor. Db/db mouse suffers from morbid obesity, but their leptin levels are significantly higher compared with ob/ob mouse. It has been often used to investigate type 2 diabetes. Zucker rat is a rat model analogous to the db/db mouse. The obese Zucker (fa/fa or ‘fatty’ rat) has abnormal extracellular domain of leptin receptor (Speakman et al. 2007). Theses rats have impaired glucose tolerance, a growth defect possibly related to a lower activity of the Growth Hormone/Insulin-like growth factor 1 axis (GH/ IGF-1 axis). Diet-induced models
Gene-modified models
High-fat and/or carbohydrate diet-induced obesity
Ob/Ob mouse (Lepob/Lepob mouse, the ‘obese’ mouse)
High-fat (HF) diet is widely known to induce obesity in animal models. When exposed to HF diet, most Sprague– Dawley rats exhibit obese-like characteristics (diet-induced obesity, DIO), but a few rats have normal body weight similar to that of control rats with a low-fat diet, and thus are called diet-resistant (DR) (Levin and Dunn-Meynell 2000). HF diet is known to rapidly and specifically reduce central actions of insulin and leptin, mainly due to a postreceptor effect (Banks et al. 2004; Hariri and Thibault 2010; Clegg et al. 2011).
A spontaneous mutation inducing obese phenotype in mouse has been investigated since the 1950s. Recently, the ob gene is considered as one of the most important genes in obese research. A single-base spontaneous mutation of the ob gene hinders the secretion of bioactive leptin which plays major role in making appetite. Leptin is mainly synthesized in white adipocyte, and its secretion is directly correlated with the amount of stored triglyceride. Leptin
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Obesity-related physiological changes
Methionine-choline deficient (MCD) rat Strictly speaking, MCD diet does not induce obesity in animal models. MCD diet can induce nonalcoholic steatohepatitis (NASH) which is a later stage of fatty liver. MCD diet promotes intrahepatic lipid accumulation by increased fatty acid uptake and decreased VLDL secretion (Rinella et al. 2008). MCD diet has been used to generate experimental NASH rodents characterized by lipid deposition and pro-inflammatory activity, which are similar to human hepatic lesion (Gomez-Lechon et al. 2009). The alterations of CYPs in diet-induced animal models of obesity are shown in Table 3.
Conclusions In this article, we comprehensively reviewed the effect of obesity on physiological factors determining drug ADME and its pharmacokinetic consequences. Oral absorption of drugs such as midazolam, propranolol and dexfenfluramine is not significantly affected by obesity. However, due to changes in body compositions, the Vd of lipophilic drugs tend to increase in obese population. Moreover, phase 1 (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) and phase 2 (UGTs and GSTs) drug metabolizing enzymes, drug transporters, hepatic/renal blood flow, and glomerular filtration rate can be affected by obesity, which can lead to alterations of hepatic/renal elimination and the CL. Therefore, those physiological changes and their pharmacokinetic consequences should be taken into account in understanding pharmacokinetics and optimizing drug therapy in obese population. Acknowledgments This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2009-0083533 and 2011-0016040).
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