Species differences in intestinal metabolic activities of cytochrome P450 isoforms between cynomolgus monkeys and humans

Drug Metab Pharmacokinet. 2011 Jun;26(3):300-6. doi: 10.2133/dmpk.DMPK-10-SH-119. Epub 2011 Mar 4.

Abstract

The oral bioavailability of some drugs is markedly lower in cynomolgus monkeys than in humans. One of the reasons for the low bioavailability in cynomolgus monkeys may be the higher metabolic activity of intestinal CYP3A; however, the species differences in intestinal metabolic activities of other CYP isoforms between cynomolgus monkeys and humans are not well known. In the present study, we investigated the intrinsic clearance (CL(int)) values in pooled intestinal microsomes from cynomolgus monkeys and humans using 25 substrates of human CYP1A2, CYP2J2, CYP2C, and CYP2D6. As in humans, intestinal CL(int) values of human CYP1A2 and CYP2D6 substrates in cynomolgus monkeys were low. On the other hand, intestinal CL(int) values of human CYP2J2 and CYP2C substrates in cynomolgus monkeys were greatly higher than those in humans. Using immunoinhibitory antibodies and chemical inhibitors, we showed that the higher intestinal CL(int) values of the human CYP2J2 and CYP2C substrates in cynomolgus monkeys might be caused by monkey CYP4F and CYP2C subfamily members, respectively. In conclusion, there is a possibility that the greatly higher metabolic activity of CYP2C and CYP4F in cynomolgus monkey intestine is one of the causes of the species difference of intestinal first-pass metabolism between cynomolgus monkeys and humans.

Publication types

  • Comparative Study

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles / metabolism
  • Amodiaquine / metabolism
  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Astemizole / metabolism
  • Biocatalysis / drug effects
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / immunology
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / immunology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Humans
  • Intestines / enzymology*
  • Isoenzymes / metabolism
  • Lansoprazole
  • Macaca fascicularis / metabolism*
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Nicardipine / metabolism
  • Nimodipine / metabolism
  • Paroxetine / metabolism
  • Pharmaceutical Preparations / metabolism*
  • Species Specificity
  • Terfenadine / metabolism

Substances

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Antibodies
  • Cytochrome P-450 Enzyme Inhibitors
  • Fatty Acids, Unsaturated
  • Isoenzymes
  • Pharmaceutical Preparations
  • cytochrome P-450 CYP2C subfamily
  • Lansoprazole
  • Amodiaquine
  • 17-octadecynoic acid
  • Paroxetine
  • Nimodipine
  • Terfenadine
  • Astemizole
  • Cytochrome P-450 Enzyme System
  • Nicardipine
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • arachidonate epoxygenase