Research Articles
The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans

https://doi.org/10.1002/jps.21708Get rights and content

Abstract

In order to elucidate the causes of the species differences in the oral bioavailability (BA) between cynomolgus monkeys and humans, the contributions of first-pass metabolism and intestinal absorption were investigated. Typical substrates of cytochrome P450 enzymes, UDP-glucuronosyltransferase enzymes and efflux transporters were selected, and the BA, the hepatic availability (Fh) and the fraction dose absorbed from gastro-intestinal tract (Fa*Fg) were calculated from pharmacokinetic analysis after oral and intravenous administration in cynomolgus monkeys. In addition, in vitro metabolism was investigated using liver and intestinal microsomes to evaluate the relationship between in vivo and in vitro results. The BA of cynomolgus monkeys was low compared with that in humans with most of the drugs tested, and not only Fh but also Fa*Fg contributed significantly to the low BA in cynomolgus monkeys. When Fh was evaluated in in vitro experiments, it correlated well with the in vivo Fh. However, although the metabolic activities of CYP3A4 substrates were high in cynomolgus monkey intestinal microsomes, those of the other substrates were low or not detected. These findings suggested that the species differences and low BA in cynomolgus monkeys could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4343–4353, 2009

Section snippets

INTRODUCTION

In the drug discovery and development process, the prediction of human bioavailability (BA) and the pharmacokinetic (PK) profiles of candidates are essential to evaluate the relationship of the PK/pharmacodynamics (PD) and exposure-toxicity in humans.1 Experimental animals, such as rats, dogs and monkeys, have been widely used to predict human PK.2, 3, 4, 5, 6 However, the large species differences in the PK profiles in experimental animals sometimes make it difficult to assess appropriate

Materials

Alprazolam, antipyrine, diclofenac sodium salt, imipramine hydrochloride, methotrexate, midazolam maleate salt, nifedipine, piroxicam, probenecid, propranolol, propafenone hydrochloride, (±)-verapamil hydrochloride and warfarin, used as an internal standard, were purchased from Sigma–Aldrich (St. Louis, MO). Cynomolgus monkey liver and intestine microsomes were purchased from Xenotech, LLC (Kansas City, KS). All other reagents were obtained from commercial sources and were of analytical or the

RESULTS

The dose and oral BAs of the sixteen drugs tested in cynomolgus monkeys and those of humans are summarized in Table 1. The data of acetaminophen, propranolol, atenolol, furosemide and naproxen were obtained from a previous report,15 and all the data on humans are cited from the literature.19, 20, 21, 22, 23, 24, 25

The BAs of atenolol, antipyrine, piroxicam and naproxen in cynomolgus monkeys were almost comparable with those in humans. Furosemide, diclofenac, alprazolam, and probenecid showed

DISCUSSION

Since the first-pass metabolism in the liver and intestine is a critical factor in determining the oral BA of drugs, species differences in hepatic and intestinal clearance would cause inaccuracies in the prediction of human BA. Chiou et al. have reported that although a large number of drugs showed significantly lower BA in monkeys, they are attributable to higher hepatic first-pass metabolism.12 On the other hand, recent reports have revealed that monkeys may provide a more qualitatively

REFERENCES (60)

  • E.S. Waller et al.

    Disposition and absolute bioavailability of furosemide in healthy males

    J Pharm Sci

    (1982)
  • F.P. Guengerich et al.

    Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism

    J Biol Chem

    (1986)
  • I. Poggesi

    Predicting human pharmacokinetics from preclinical data

    Curr Opin Drug Discov Dev

    (2004)
  • S.A. Roberts

    Drug metabolism and pharmacokinetics in drug discovery

    Curr Opin Drug Discov Dev

    (2003)
  • R.M. Ings

    Interspecies scaling and comparisons in drug development and toxicokinetics

    Xenobiotica

    (1990)
  • I. Mahmood

    Can absolute oral bioavailability in humans be predicted from animals? A comparison of allometry and different indirect methods

    Drug Metabol Drug Interact

    (2000)
  • I. Mahmood et al.

    Interspecies allometric scaling. Part I. Prediction of clearance in large animals

    J Vet Pharmacol Ther

    (2006)
  • H. Tang et al.

    A novel model for prediction of human drug clearance by allometric scaling

    Drug Metab Dispos

    (2005)
  • W.K. Sietsema

    The absolute oral bioavailability of selected drugs

    Int J Clin Pharmacol Ther Toxcol

    (1989)
  • H. Kondo et al.

    Gastrointestinal transit of liquids in unfed cynomolgus monkeys

    Biopharm Drug Dispos

    (2003)
  • K. Ikegami et al.

    Suitability of the cynomolgus monkey as an animal model for drug absorption studies of oral dosage forms from viewpoint of gastrointestinal physiology

    Biol Pharm Bull

    (2003)
  • W.L. Chiou et al.

    Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats

    Pharm Res

    (1998)
  • W.L. Chiou et al.

    Evaluation of using dogs as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans

    Pharm Res

    (2000)
  • W.L. Chiou et al.

    Comparison of oral absorption and bioavailability of drugs between monkey and human

    Pharm Res

    (2002)
  • K.W. Ward et al.

    A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. I. Clearance

    Drug Metab Dispos

    (2004)
  • J.E. Sharer et al.

    Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey

    Drug Metab Dispos

    (1995)
  • M. Takahashi et al.

    Characterization of gastrointestinal drug absorption in cynomolgus monkeys

    Mol Pharm

    (2008)
  • B. Davies et al.

    Physiological parameters in laboratory animals and humans

    Pharm Res

    (1993)
  • Y. Naritomi et al.

    Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans

    Drug Metab Dispos

    (2001)
  • T. Iwatsubo et al.

    Prediction of in vivo hepatic metabolic clearance of YM796 from in vitro data by use of human liver microsomes and recombinant P-450 isozymes

    J Pharmacol Exp Ther

    (1997)
  • J.G. Hardman et al.

    Goodman and Gilman's The Pharmacological Basis of Therapeutics

    (2001)
  • C. Dollery

    Therapeutic drugs

    (1999)
  • S. Vozeh et al.

    Nonlinear kinetics of propafenone metabolites in healthy man

    Eur J Clin Pharmacol

    (1990)
  • M. Eichelbaum et al.

    Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D,L-verapamil using stable isotope-labelled verapamil

    Eur J Clin Pharmacol

    (1981)
  • M. Eichelbaum et al.

    Pharmacokinetics and metabolism of Antipyrine (phenazone) after intravenous and oral administration

    Arzneimittelforschung

    (1982)
  • W.D. Mason et al.

    Kinetics and absolute bioavailability of atenolol

    Clin Pharmacol Ther

    (1979)
  • M.H. Court et al.

    Interindividual variability in acetaminophen glucuronidation by human liver microsomes: Identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms

    J Pharmacol Exp Ther

    (2001)
  • C.K. Gelotte et al.

    Disposition of acetaminophen at 4, 6 and 8 g/day for 3 days in healthy young adults

    Clin Pharmacol Ther

    (2007)
  • S. Kumar et al.

    Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: Role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide

    J Pharmacol Exp Ther

    (2002)
  • H. Stierlin et al.

    Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites

    Xenobiotica

    (1979)
  • Cited by (0)

    View full text