Effects of silybinin, CYP3A4 and P-glycoprotein inhibitor in vitro, on the bioavailability of loratadine in rats.
The effect of silybinin on the pharmacokinetics of orally and intravenously administered loratadine in rats was investigated. Pharmacokinetic parameters of loratadine were determined in rats following oral (4 mg x kg(-1)) and intravenous (1 mg x kg(-1)) administration to rats in the presence and absence of silybinin (0.3, 1.5 and 6 mg x kg(-1)). Compared to those animals in an oral control group (given loratadine alone), the area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C(max)) of loratadine were increased significantly (P < 0.05 for 1.5 mg x kg(-1), P < 0.01 for 6 mg x kg(-1)) by 50.0-76.7% and 65.4-90.1%, respectively, by silybinin. Consequently, the absolute bioavailability of loratadine in the presence of silybinin (1.5 and 6 mg x kg(-1)) was 8.6-10.2%, which was significantly (1.5 mg x kg(-1), P < 0.05; 6 mg x kg(-1), P < 0.01) enhanced compared to that in oral control group (5.8%). Moreover, the relative bioavailability of loratadine was 1.50- to 1.77-fold greater than that in the control group. In contrast, silybinin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that coadministration of silybinin could inhibit the cytochrome P450 (CYP) 3A4-mediated metabolism of loratadine, resulting in reducing gastrointestinal and hepatic first-pass metabolism, and the P-glycoprotein (P-gp) efflux pump in the small intestine. Silybinin significantly enhanced the oral bioavailability of loratadine, suggesting that concurrent use of silybinin and loratadine should be monitored closely for potential drug interactions.
Li
C
C
College of Pharmacy, Yanbian University, Jilin, China.
Lee
M Y
MY
Choi
J S
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D005456:Fluorescent Dyes; D006207:Half-Life; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D017336:Loratadine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000975:Antioxidants; D065607:Cytochrome P-450 Enzyme Inhibitors; D005456:Fluorescent Dyes; D039563:Histamine H1 Antagonists, Non-Sedating; D012838:Silymarin; D020112:Rhodamine 123; D000077385:Silybin; D017336:Loratadine; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A