Interaction of Anti-HIV Protease Inhibitors With the Multidrug Transporter P-Glycoprotein (P-gp) in Human Cultured Cells

Abstract

The anti-HIV protease inhibitors represent a new class of agents for treatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfinavir are the first drugs approved in this class and significantly reduce HIV RNA copy number with minimal adverse effects. They are all substrates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly expressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for this transporter. To determine whether these protease inhibitors are modulators of P-gp, we studied them in cell lines which do and do not express P-gp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [3H]paclitaxel and [3H]vinblastine in P-gp-positive cells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling studies, saquinavir and ritonavir displaced [3H]azidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquinavir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

“…In vitro, PIs undergo metabolic extraction by CYP3A4 in the gut wall and are also substrates for and inhibitors of intestinal P-gp (Kim et al, 1998;Lee et al, 1998;Washington et al, 1998;Shiraki et al, 2000). Our analysis of the ACTG 378 data (model M2 versus M1 or M4 versus M3) is compatible with gut-level interactions as well as hepatic ones.…”

“…Each of the three drugs are possible substrates for both gut CYP3A4 and P-gp (Wacher et al, 1995;Kim et al, 1998;Lee et al, 1998;Washington et al, 1998;Shiraki et al, 2000) and hence have the potential to inhibit their action on the other two drugs. Inhibition of CYP3A (P-gp) in the gut would be expected to increase the F gut of a drug extensively metabolized (back-transported into the gut lumen) by it.…”

“…Protease inhibitors (PIs 1 ) ritonavir (R), nelfinavir (N), and saquinavir (S) are primarily metabolized by CYP3A4 (and partially by other cytochromes P450) in the liver (Eagling et al, 1997;Fitzsimmons and Collins, 1997;Hsu et al, 1998a;Kim et al, 1998;Washington et al, 1998). They exhibit extensive pharmacokinetic (PK) interactions (Merry et al, 1997;Hsu et al, 1998b;Jarvis et al, 1998), but the degree to which those interactions occur at the level of hepatic metabolism, gut metabolism, or gut efflux transporters is still uncertain.…”

“…Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1) R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2) N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.Protease inhibitors (PIs 1 ) ritonavir (R), nelfinavir (N), and saquinavir (S) are primarily metabolized by CYP3A4 (and partially by other cytochromes P450) in the liver (Eagling et al, 1997;Fitzsimmons and Collins, 1997;Hsu et al, 1998a;Kim et al, 1998;Washington et al, 1998). They exhibit extensive pharmacokinetic (PK) interactions (Merry et al, 1997;Hsu et al, 1998b;Jarvis et al, 1998), but the degree to which those interactions occur at the level of hepatic metabolism, gut metabolism, or gut efflux transporters is still uncertain.…”

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

“…[2][3][4]12,[14][15][16] Protease inhibitors are known inhibitors of CYP3A and p-glycoprotein. 17 The initial HAART regimen consisted of a combination of NRTI and NNRTI without or with one PI. Recently, a combination of two PIs (lopinavir and ritonavir), both of which are metabolized by the CYP3A enzyme system, has been increasingly used.…”