title: Evidence for time-dependent interactions between ritonavir and lopinavir/ritonavir plasma levels following P-glycoprotein inhibition in Sprague-Dawley rats.
abstract: The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1: ritonavir, 20 mg/kg/d (n=18), group 2: ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3: LPV/r, 80 and 20 mg/kg/d (n=17) and group 4: LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 µg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p<0.005) and chronic treatment (day 21) (p<0.005). During acute (but not chronic) LPV/r treatment, verapamil also increased the lopinavir levels (p<0.05). A time or exposure dependent pharmacokinetic interaction was thus observed between verapamil and ritonavir whether administered alone or after the lopinavir-ritonavir combination (LPV/r). This interaction occurred most prominently after acute treatment, and became less pronounced over time. This study indicates the importance of a longer time frame to investigate enzyme based drug interactions in rat models.
authors.affiliation: Unit for Drug Research and Development, Division of Pharmacology, School of Pharmacy, North-West University, Potchefstroom, 2520, South Africa.
authors.forename: Michael
authors.initials: M
authors.lastname: du Plooy
authors.forename: Michelle
authors.initials: M
authors.lastname: Viljoen
authors.forename: Malie
authors.initials: M
authors.lastname: Rheeders
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004334:Drug Administration Schedule; D061466:Lopinavir; D008297:Male; D011744:Pyrimidinones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D002121:Calcium Channel Blockers; D011744:Pyrimidinones; D061466:Lopinavir; D014700:Verapamil; D019438:Ritonavir