Effect of Grapefruit Juice and Ritonavir on Pharmacokinetics of Lopinavir in Wistar Rats

Abstract

Lopinavir (LPV), a newer HIV protease inhibitor, has poor bioavailability being a substrate of both cytochrome P450 3A enzyme system (CYP3A) and permeability-glycoprotein (P-gp). Ritonavir (RTV) is a known inhibitor of both P-gp and CYP3A and is co-administered with LPV in anti-HIV therapy. Grapefruit juice (GFJ) is known to inhibit CYP3A and has conflicting effects, ranging from activation to inhibition, on P-gp. In this research work, the effects of GFJ and RTV on the pharmacokinetics of LPV were compared in rats. A mechanistic evaluation was undertaken using various in vitro and ex vivo studies to support the in vivo pharmacokinetic data. The plasma levels of LPV were found to increase significantly upon co-administration with GFJ in single dose as well as multidose pretreatment studies. Similar, but marginally higher, results were observed upon co-administration of LPV with RTV. No significant change in t(max) was observed in the various treatment groups. The apparent permeability of LPV in the ileum increased significantly after the pre-incubation with GFJ and RTV compared with no pre-incubation. The GFJ and RTV showed a significant and similar inhibitory effect on rat intestinal microsomes in the metabolism of LPV. The GFJ was equally effective as RTV in increasing the bioavailability of LPV.

Mechanisms underlying food–drug interactions: Inhibition of intestinal metabolism and transport

“…The lack of effect in the imatinib study could be attributed to the same reason a lack of effect was observed initially in the sirolimus study. A recent study in rats suggested that GFJ may be equally effective as ritonavir in increasing the bioavailability of the HIV protease inhibitor lopinavir (Ravi et al, 2012). Again, like the aforementioned studies, the GFJ was not analyzed for furanocoumarin content.…”

Comparative pharmacokinetic evaluation of lopinavir and lopinavir-loaded solid lipid nanoparticles in hepatic impaired rat model

“…Major reason contributing to the high extraction of free LPV appears to be due to rapid metabolism of drug in liver. From the previously published literatures and our data, it is evident that any functional damage to liver would reduce LPV's clearance and could elevate drug plasma exposure.…”

“…It is an integral part of HAART regimen and a new standard of care for HIV‐infected patients . LPV shows poor plasma exposure after oral administration and high interpatient variability in humans due to its low aqueous solubility, extensive presystemic metabolism and P‐gp efflux . As a result, when given alone in conventional formulation (tablet and solution), it fails to achieve therapeutic concentration in blood and target viral reservoirs leading to a poor clinical outcome of the therapy …”

Enhanced Boosting of Oral Absorption of Lopinavir Through Electrospray Coencapsulation with Ritonavir

“…Low bioavailability and fast elimination are observed when lopinavir alone is orally administered; however, coadministration with ritonavir dramatically improves poor pharmacokinetic properties of lopinavir . Numerous studies demonstrated that ritonavir enhanced the transport of lopinavir from the intestinal lumen to the systemic circulation through inhibition of presystemic and systemic metabolism of lopinavir, which is a substrate of CYP3A . The findings form rationales for the therapy of HIV infection by lopinavir with a subtherapeutic dose of ritonavir, which results in increased and sustained plasma levels of lopinavir.…”