Inter-individual differences of 4-[4-(4-methylphenyl)-phenylmethoxy-1-piperidinyl]butyric acid disposition in rats: possible involvement of genetic polymorphism.
Inter-individual differences of drug plasma concentration were recognized in outbred rats after an oral or intravenous administration of (+)-4-[4-(4-methylphenyl)phenylmethoxy-1-piperidinyl]butyric acid hydrochloride ((+)-MPPB). Rats could be divided into two phenotypes, the rapid metabolizing (RM) group and the slow metabolizing (SM) group. The hepatic clearance of RM-phenotyped Sprague-Dawley rats was about 10 times larger than that of the SM group. Outbred male and female Sprague-Dawley rats and male Wistar rats were mixtures of the RM and SM groups. On the other hand, all inbred male Lewis rats were RM, and all inbred male F344 and ACI rats were SM. This study was undertaken to investigate the inter-individual differences of (-)-MPPB and the metabolic pathways of (+)- and (-)-MPPB. When (-)-MPPB was orally administered to male Sprague-Dawley rats, similar inter-individual differences of plasma concentration were recognized. RM-phenotyped Sprague-Dawley rat liver microsomes metabolized (+)-MPPB to 4-hydroxymethylphenyl-MPPB (M1), and (-)-MPPB to M1 and 4'-hydroxyphenyl-MPPB (M2). The formation of these metabolites was less with SM-phenotyped than with RM-phenotyped Sprague-Dawley rat liver microsomes. The kinetic parameters of M1 formation from (+)-MPPB by RM-phenotyped rat liver microsomes were characteristic of a two-enzyme system with a 100-fold difference in their affinities (KM values). On the other hand, SM-phenotyped rats have only the low-affinity enzyme system. An inhibition study demonstrated that both enzymes were cytochrome P450.(ABSTRACT TRUNCATED AT 250 WORDS)
Takahara
E
E
Research and Development Division, Hokuriku Seiyaku Co., Ltd., Tokyo, Japan.
Nagata
O
O
Kato
H
H
Ohta
S
S
Hirobe
M
M
D000284:Administration, Oral; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
C090637:4-(4-(4-methylphenyl)phenylmethoxy-1-piperidinyl)butyric acid; D001559:Benzhydryl Compounds