Enantioselective uptake of BOF-4272, a xanthine oxidase inhibitor with a chiral sulfoxide, by isolated rat hepatocytes.
The transport mechanisms of the enantiomers of BOF-4272, a new drug for the treatment of hyperuricemia, were studied using freshly prepared rat hepatocytes. BOF-4272 consists of S(-) and R(+) enantiomers due to a chiral center in the sulfoxide moiety. The uptake of these BOF-4272 enantiomers by hepatocytes was found to be temperature and dose dependent. The temperature-dependent uptake of the S(-) and R(+) enantiomers showed saturation kinetics. The Km values for the S(-) and R(+) enantiomers were 59.3 and 25.7 microM, respectively, which was a significant difference (p < 0.05). However, the maximal uptake rate was comparable for both enantiomers. Metabolic inhibitors such as antimycin, oligomycin, rotenone, carbonylcyanide m-chlorophenyl hydrazone, and carbonyl cyanide-p-(trifluromethoxy)-phenylhydrazone significantly inhibited uptake of the R(+) enantiomer, but had little effect on uptake of the S(-) enantiomer. Ouabain (an inhibitor of Na+/K(+)-ATPase) and p-nitrobenzylthioinosine (NBMPR, a nucleoside transporter inhibitor) showed no significant effects on the uptake of either enantiomer. Organic anions such as taurocholate and cholate reduced the uptake of both enantiomers. These results suggest that the hepatic uptake of both BOF-4272 enantiomers is not due to simple diffusion but also involves carrier-mediated uptake. We suggest that the carrier-mediated uptake of BOF-4272 enantiomers includes both NBMPR-insensitive facilitated diffusion and an active transport system in liver plasma membrane, and that the enantioselective uptake of BOF-4272 is due to differences in affinity for the active transporter.
Naito
S
S
Laboratory of Drug Metabolism Research, Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima 772-8601, Japan.
Nishimura
M
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012451:Safrole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013696:Temperature; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014227:Triazines; C072977:BOF 4272; D014969:Xanthine Oxidase; D012451:Safrole; C005746:sulfoxide