Pharmacokinetics of dl-praeruptorin A after single-dose intravenous administration to rats with liver cirrhosis

ABSTRACT

As a novel drug in the treatment of cardiac diseases, dl-praeruptorin A [Pd-Ia] is the major active component of traditional herbal medicine Peucedanum praeruptorum Dunn and is metabolized primarily via cytochrome P450 isozymes [CYP] 3A1 and 3A2 in rats. In the present study, the influence of liver cirrhosis on pharmacokinetics of Pd-Ia and hepatic mRNA expression of CYP3A1 and 3A2 in rats with experimental liver cirrhosis [LC rats] were evaluated. Pd-Ia was given intravenously [5 mgúkg-1] to LC rats induced by dimethylnitrosamine and pharmacokinetic variables were measured. Enzyme kinetic metabolism of Pd-Ia in rat hepatic microsomes was also investigated and hepatic mRNA expression of CYP3A1 and 3A2 were measured by real-time PCR. After intravenous administration in LC rats, the area under the plasma concentration-time curve from time zero to infinity [AUC0-infinity] was significantly greater than that in control rats, which might be due to slower rate of the hepatic blood flow and significant slower hepatic intrinsic clearance [CL int] in rats. The decreased metabolic clearance of Pd-Ia in LC rats might be at least partly caused by the decreased levels of CYP3A1 and 3A2 responsible for Pd-Ia metabolism. These findings may provide new insights into the inter- and intra-individual pharmacokinetic variability of Pd-Ia