Comparison of human and rhesus monkey in vitro phase I and phase II hepatic drug metabolism activities.
Twelve human and six rhesus monkey liver samples were analyzed in vitro for phase I metabolism and phase II conjugation activity. Of the eight P-450-dependent activities measured, only N-nitrosodimethylamine N-demethylase activity was not significantly different between the two species. Coumarin 7-hydroxylase activity was greater in the human as compared with the rhesus monkey samples, whereas erythromycin N-demethylase, benzphetamine N-demethylase, pentoxyresorufin O-dealkylase, ethoxycoumarin O-deethylase, and ethoxyresorufin O-deethylase activities were significantly greater in rhesus monkey microsome samples (p < or = 0.01). Cimetidine S-oxygenation and chlorpromazine N-oxygenation were 2.1- and 2.6-fold higher in rhesus monkey samples. Of the seven microsomal and cytosolic phase II activities measured, only 17 alpha-ethynylestradiol glucuronidation was significantly higher in the human samples. The genetic polymorphism for isoniazid acetylation was evident only in the human samples, with activities varying 200-fold. This study shows that, although the rhesus monkey is often used by the pharmaceutical industry as a representative mammalian species for drug testing, the in vitro metabolic capabilities of the human and rhesus monkey drug metabolizing enzymes are different.
Stevens
J C
JC
Department of Drug Metabolism and Disposition, Eli Lilly and Company, Indianapolis, IN 46285.
Shipley
L A
LA
Cashman
J R
JR
Vandenbranden
M
M
Wrighton
S A
SA
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D010105:Oxygenases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)