Research ArticlesThe species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans
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)
- et al.
Disposition and absolute bioavailability of furosemide in healthy males
J Pharm Sci
(1982) - 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) Predicting human pharmacokinetics from preclinical data
Curr Opin Drug Discov Dev
(2004)Drug metabolism and pharmacokinetics in drug discovery
Curr Opin Drug Discov Dev
(2003)Interspecies scaling and comparisons in drug development and toxicokinetics
Xenobiotica
(1990)Can absolute oral bioavailability in humans be predicted from animals? A comparison of allometry and different indirect methods
Drug Metabol Drug Interact
(2000)- et al.
Interspecies allometric scaling. Part I. Prediction of clearance in large animals
J Vet Pharmacol Ther
(2006) - et al.
A novel model for prediction of human drug clearance by allometric scaling
Drug Metab Dispos
(2005) The absolute oral bioavailability of selected drugs
Int J Clin Pharmacol Ther Toxcol
(1989)- et al.
Gastrointestinal transit of liquids in unfed cynomolgus monkeys
Biopharm Drug Dispos
(2003)