Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors

L, Profit; Eagling, V.A.; Back, David

doi:10.1097/00002030-199909100-00004

Cited by 146 publications

(106 citation statements)

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“…© 2007 American Association for Cancer clincancerres.aacrjournals.org Downloaded from systemic clearance of imatinib in mice (33). Because ritonavir is a known inhibitor of both ABCB1 and ABCG2 (34,35), the current data suggest that modulation of the activity of these transporters in humans would not result in substantially altered exposure to imatinib under steady-state conditions.…”

Section: Discussionmentioning

confidence: 73%

Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib

Erp

Gelderblom

Karlsson

et al. 2007

Clinical Cancer Research

104

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Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days1and 4 were 42.6 (33.0-54.9) AgÁh/mL and 41.2 (32.1-53.1) AgÁh/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 Amol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.The first rationally designed inhibitor of a signal transduction pathway, imatinib, is a competitive inhibitor of Bcr-Abl, platelet-derived growth factor receptors (a and h), and c-KIT receptor tyrosine kinases (1 -4). It was first approved for the treatment of Philadelphia chromosome -positive chronic myelogenous leukemia and, shortly thereafter, for c-KITpositive metastatic and unresectable gastrointestinal stromal tumor (5, 6).The pharmacokinetic properties of imatinib have been investigated in healthy volunteers and in patients with chronic myelogenous leukemia, gastrointestinal stromal tumor, and other tumors (7,8). Imatinib is well absorbed after oral administration with a bioavailability exceeding 90% (9). It is extensively metabolized, with up to 80% of the administered dose being recovered in feces, predominantly as metabolites (10). Imatinib is metabolized in vitro principally by cytochrome P450 (CYP) 3A4 and CYP3A5, with CYP1A2, CYP2C9, CYP2C19, and CYP2D6 playing a minor role (8). The main circulating metabolite of imatinib is an N-desmethyl derivative, CGP74588, which has in vitro activity similar to that of imatinib, and the systemic exposure represents approximately 10% to 15% of that for imatinib (10). The pharmacokinetic profile of a single dose of imatinib is sensitive to CYP3A4 modulation, with a 74% and 30% reduction in imatinib area under the curve (AUC) observed with coadministrati...

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Section: Discussionmentioning

confidence: 73%

Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib

Erp

Gelderblom

Karlsson

et al. 2007

Clinical Cancer Research

104

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“…PIs, however, have minimal effects on CYP2B6. Recent data indicate that most PIs are substrates for the P-gp drug efflux pump, and ritonavir has even been reported to be a potent P-gp inhibitor [21][22][23]. Thus, a multiple dose study on efavirenz and ritonavir in combination in healthy volunteers found ritonavir increased the AUC of efavirenz by 20% [2].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Forrest

Rosenkranz

et al. 2007

Biopharm & Drug Disp

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The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CL t /F), volume of distribution at steady state (V ss /F), intercompartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CL t /F and V ss /F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CL t /F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean V ss /F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in V p /F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.

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“…Besides being substrates of CYP, PIs are also substrates and can act as inhibitors of Pglycoprotein, a transmembrane glycoprotein that functions as an energy-dependent efflux pump for a wide variety of structurally unrelated compounds. [53][54][55] Furthermore, the multidrug resistance associated proteins, MRP1 and possibly MRP2, are known to be involved in the disposition of the PIs. [53] These transporter proteins are also involved in drug efflux.…”

Section: Protease Inhibitorsmentioning

confidence: 99%