Change of drug excretory pathway by CCl4-induced liver dysfunction in rat.
Liver dysfunction affects the pharmacokinetics of drugs. The liver plays an important role in drug excretion as well as drug metabolism and pharmacokinetics. In the present study, the relationship between changes in the cefmetazole (CMZ) excretory pathway and the degree of liver dysfunction induced by CCl(4) treatment was investigated. CMZ is mainly excreted as an unchanged form in feces in control rats. Depending on the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), urinary CMZ excretion was increased, whereas fecal CMZ excretion was decreased in rat with liver dysfunction. The AUC of CMZ in rats with severe liver dysfunction was approximately 2-fold higher than that in control rats. Since drug transporters could be involved in drug excretion, changes in the expression of representative hepatic drug transporters in liver dysfunction were investigated by rat DNA microarray. Basolateral solute carrier transporters such as Ntcp, Oct1, and Oatp2 were decreased and basolateral ATP-binding cassette transporters such as Mrp3 and Mrp4 were increased by the CCl(4) treatment. On the other hand, canalicular Mrp2 and Bsep were decreased, but Mdr1 was increased. However, the transporter system for CMZ has not been identified yet. In conclusion, we clarified that the fecal and urinary excretory profiles of CMZ were changed clearly depending on the serum AST and ALT levels in liver dysfunction. The changes in the CMZ excretory pathway might be responsible for the changes in the expression of drug transporters.
Okumura
Hirotoshi
H
Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Katoh
Miki
M
Minami
Keiichi
K
Nakajima
Miki
M
Yokoi
Tsuyoshi
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D001483:Base Sequence; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D015311:Cefmetazole / Q000493:pharmacokinetics*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D017931:DNA Primers; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
D000900:Anti-Bacterial Agents; D017931:DNA Primers; D012333:RNA, Messenger; D015311:Cefmetazole; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase