Effect of chronic administration of phenobarbital on the hepatobiliary transport of phenol red: assessment by statistical moment analysis.
The effect of enzyme induction on the hepatobiliary transport of phenol red (PR) in rats was investigated by application of a new analytical system to determine local drug disposition based on statistical moment theory (T. Kakutani et al., J. Pharmacokin. Biopharm. 13:609-631, 1985). Employing the moment parameters obtained from the time courses of plasma and biliary concentrations of PR and its metabolite after intravenous injection, the hepatobiliary transport of PR was theoretically assessed by separating it into component subprocesses such as hepatic uptake, hepatobiliary transfer, and intrahepatic metabolism. The results demonstrated that the acceleration of plasma disappearance of PR caused by pretreatment with phenobarbital (PB), known to induce hepatic enzyme systems, could be attributed to elevation of both hepatic and extrahepatic clearances. While PB did cause bile flow elevation (choleresis) and increased metabolism, these effects were shown to make little contribution to accelerated plasma disappearance of PR, since it was shown that the hepatobiliary excretion of PR was rate-limited by the intrahepatic transfer process, which was unaffected by PB treatment. From the results of this study, this experimental/analysis methodology seems to be useful in obtaining detailed information about hepatobiliary transport of the drug from in vivo data.
Kakutani
T
T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Endo
K
K
Nara
E
E
Nakazora
S
S
Hashida
M
M
D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology*; D010637:Phenolsulfonphthalein / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013223:Statistics as Topic / Q000379:methods; D013997:Time Factors
D010637:Phenolsulfonphthalein; D010634:Phenobarbital