ritonavir and fexofenadine

We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC0-24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)0-24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.

Topics: Adult; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chromatography, Liquid; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; HIV Protease Inhibitors; Humans; Intestines; Liver; Liver-Specific Organic Anion Transporter 1; Male; Midazolam; Organic Anion Transporters; Pravastatin; Ritonavir; Saquinavir; Tandem Mass Spectrometry; Terfenadine; Young Adult

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.

Topics: Adult; Alfentanil; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Intestines; Liver; Male; Methadone; Narcotics; Pupil; Ritonavir; Stereoisomerism; Terfenadine

Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.. This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively.. Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C(max) by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.. Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Ginkgo biloba; HIV Protease Inhibitors; Humans; Lopinavir; Male; Midazolam; Phytotherapy; Plant Extracts; Protease Inhibitors; Pyrimidinones; Ritonavir; Terfenadine

This study investigated the effect of single-dose and steady-state lopinavir/ritonavir on the exposure to fexofenadine, as a measure of P-glycoprotein activity. Sixteen volunteers (8 women) received single-dose oral fexofenadine 120 mg alone, in combination with single-dose ritonavir 100 mg or lopinavir/ritonavir 400/100 mg (randomized 1:1, stratified by sex), and in combination with steady-state lopinavir/ritonavir 400/100 mg twice daily. Single-dose ritonavir and lopinavir/ritonavir increased the area under the fexofenadine plasma concentration-time curve from 0 to infinity (AUC(infinity)) by 2.2- and 4.0-fold, respectively (P < .02). Steady-state lopinavir/ritonavir increased the fexofenadine AUC(infinity) by 2.9-fold. No changes were observed in the fexofenadine elimination half-life (P > .12). The fexofenadine AUC(infinity) was increased by lopinavir/ritonavir, likely due to increased bioavailability secondary to P-glycoprotein inhibition. After repeated administration of lopinavir/ritonavir, the interaction was attenuated compared to the single-dose effect, although a net inhibitory effect was maintained. Time-dependent inhibition of P-glycoprotein by lopinavir/ritonavir should be considered when P-glycoprotein substrates are coadministered.

Topics: Administration, Oral; Adult; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Drug Combinations; Drug Interactions; Female; Genotype; Histamine H1 Antagonists; HIV Protease Inhibitors; Humans; Liver; Lopinavir; Male; Middle Aged; Organic Anion Transporters; Pyrimidinones; Ritonavir; Terfenadine; Time Factors

  Ritonavir dramatically increases the bioavailability of a variety of concurrently administered drugs by inhibition of metabolic enzymes and drug transporters. The purpose of this study was to investigate the extent to which ritonavir's inhibition of drug transporters and/or CYP3A contributes to the increased oral bioavailability in mice. The area under the plasma concentration-time curves (AUC) for orally administered saquinavir after coadministration with 50 mg/kg ritonavir dramatically increased (325-fold). As a result, the bioavailability, Fa·Fg and Fh increased 75-, 38- and twofold, respectively. In addition, the increase in the AUC predicted from the in vitro Ki value was ninefold, which was derived from the inhibition of metabolic enzymes by ritonavir in the liver. The remaining 36-fold increase in the AUC was considered to be derived from the inhibition in the small intestine. The AUCinf for probe substrate midazolam, fexofenadine, and pravastatin increased after the oral administration of ritonavir by only five-, 13-, and sevenfold, respectively. Moreover, the AUC0-12 for saquinavir was affected negligibly by itraconazole. These results indicate ritonavir mainly affects the first-pass effect of saquinavir in the small intestine, increasing the bioavailability of orally administered saquinavir. Furthermore, cyp isoforms other than CYP3A, which contribute to the metabolism of saquinavir in humans, are involved in the metabolism of saquinavir in mice.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B; Biological Availability; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Protease Inhibitors; Inactivation, Metabolic; Mice; Microsomes; Midazolam; Pravastatin; Ritonavir; Saquinavir; Terfenadine

This study investigated fexofenadine (FXD) transport and the inhibition of FXD transport in Caco-2 cell monolayer transwells, using rhodamine 123 (RH123) transport as a positive control. FXD transport from the basolateral (B) to apical (A) compartment was fivefold higher than A to B transport. FXD transport was linear with respect to time (up to 270 min) and concentration (up to 300 microm). Similar results were seen with the positive control RH123. Ritonavir (100 PM) and verapamil (100 microm) reduced transport of FXD and RH123 by more than 80%, whereas transport was not inhibited by 100 m indomethacin or 2 mM probenecid. This suggests predominantly P-glycoprotein (P-gp)-mediated transport as opposed to transport by multidrug resistance protein. In concentration-response experiments, FXD transport was inhibited by verapamil and ritonavir with IC50 values of 6.5 microm and 5.4 microm, respectively. Results from this in vitro study demonstrate differential transport of FXD across Caco-2 cell monolayers and inhibition of FXD transport by established P-gp inhibitors. Thefindings support the use of FXD as an index or probe compound to reflect P-gp activity in vivo.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Caco-2 Cells; Chromatography, High Pressure Liquid; Depression, Chemical; Drug Interactions; Drug Stability; Fluorometry; Histamine H1 Antagonists; Humans; In Vitro Techniques; Kinetics; Rhodamines; Ritonavir; Terfenadine; Time Factors; Verapamil

Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition. Utilizing a recombinant vaccinia expression system, members of the organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug's plasma and brain levels, respectively, compared with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.

Topics: Animals; Anion Transport Proteins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Caco-2 Cells; Carrier Proteins; Genes, MDR; HeLa Cells; Histamine H1 Antagonists; Humans; LLC-PK1 Cells; Mice; Rats; Swine; Terfenadine; Tissue Distribution; Transfection; Vaccinia virus