title: Regional distribution of drug-metabolizing enzyme activities in the liver and small intestine of cynomolgus monkeys.
abstract: The cynomolgus monkey is an animal species widely used to study drug metabolism because of its evolutionary closeness to humans. However, drug-metabolizing enzyme activities have not been compared in various parts of the liver and small intestine in cynomolgus monkeys. In this study, therefore, drug-metabolizing enzyme activities were analyzed in the liver (the five lobes) and small intestine (six sections from the duodenum to the distal ileum). 7-Ethoxyresorufin O-deethylation, coumarin 7-hydroxylation, paclitaxel 6α-hydroxylation, diclofenac 4'-hydroxylation, tolbutamide methylhydroxylation, S-mephenytoin 4'-hydroxylation, bufuralol 1'-hydroxylation, chlorzoxazone 6-hydroxylation, midazolam 1'-hydroxylation, and testosterone 6β-, 16α-, 16β-, and 2α-hydroxylation were used as the probe reactions for this investigation. In liver, all probe reactions were detected and enzyme activity levels were similar in all lobes, whereas, in the small intestine, all enzyme activities were detected (except for coumarin 7-hydroxylase and testosterone 16α-hydroxylase activity), but from jejunum to ileum there was a decrease in the level of enzyme activity. This includes midazolam 1'-hydroxylation and testosterone 6β-hydroxylation, which are catalyzed by cynomolgus monkey cytochrome P450 (CYP) 3A4/5, orthologs of human CYP3A4/5, which are important drug-metabolizing enzymes. The data presented in this study are expected to facilitate the use of cynomolgus monkeys in drug metabolism studies.
authors.affiliation: Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Akinori
authors.initials: A
authors.lastname: Matsushita
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Matsuno
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Utoh
authors.forename: Chika
authors.initials: C
authors.lastname: Nakamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D055162:Biocatalysis; D002753:Chlorzoxazone / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004008:Diclofenac / Q000378:metabolism; D004386:Duodenum / Q000201:enzymology; D007082:Ileum / Q000201:enzymology; D007421:Intestine, Small / Q000201:enzymology*; D007583:Jejunum / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis / Q000378:metabolism*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014044:Tolbutamide / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; C400322:cytochrome P-450 CYP2C subfamily; D004008:Diclofenac; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C025619:steroid 16-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; C043872:bufuralol 1'-hydroxylase; D002753:Chlorzoxazone; D017239:Paclitaxel; D008617:Mephenytoin; D008874:Midazolam