Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell line

Perloff, Michael D.; Moltke, Lisa L. von; Marchand, James E.; Greenblatt, David J.

doi:10.1002/jps.1133

Cited by 123 publications

(55 citation statements)

References 45 publications

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“…In fact, PIs are known to interact with efflux transporters such as P-glycoprotein (Pgp) and multidrug resistance-associated proteins (7,18,19,26,33,47). LPV and ritonavir could thus affect TDF absorption by inhibiting Pgp activity, as previously observed in in vitro experiments (43).…”

Section: Discussionmentioning

confidence: 99%

Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir

Pruvost

Negredo

Théodoro

et al. 2009

Antimicrob Agents Chemother

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Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC 0-4 ), the maximum concentration of the drug (C max ), and the residual concentration of the drug at the end of the dosing interval (C trough ) for plasma and the AUC 0-4 and C trough for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC 0-4 was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C trough values for women.Highly active antiretroviral therapy regimens include at least three antiretroviral agents combining a nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI] backbone with a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (51). The issue of drug-drug interaction between NRTIs, including N(t)RTIs, and also between N(t)RTIs and PIs or NNRTIs needs to be addressed (37).All these drugs or prodrugs could interact at the systemic level (absorption, metabolism, distribution, or elimination) or at the cellular level through membrane transport, or through intracellular metabolism for the N(t)RTIs.Several in vitro and in vivo intracellular interactions have been reported between NRTIs sharing the same metabolic pathways for thymidine analogues (14, 17) and for cytidine analogues (24).More recently, a significant interaction between didanosine (ddI) and tenofovir (TFV) disoproxil fumarate (TDF) has been clinically demonstrated (6,23,29,32), showing a higher plasma exposure to ddI when it is combined with TD...

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Section: Discussionmentioning

confidence: 99%

Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir

Pruvost

Negredo

Théodoro

et al. 2009

Antimicrob Agents Chemother

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“…Ritonavir exposure causes a concentration-dependent induction in MRP1 protein and decreased ritonavir accumulation by LS-180V intestinal carcinoma cells (Perloff et al, 2001). It is notable that an overexpression of MRP1 in CEM cells is associated with a considerable increase in productive HIV-1 infection (Speck et al, 2002).…”

Section: Hiv/aidsmentioning

confidence: 99%

Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System

Dallas

Miller²,

Bendayan³

2006

Pharmacol Rev

267

207

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“…The interactions of protease inhibitors with Pgp and ABCCs have been extensively studied, and it has been shown that they are either substrates or modulators of efflux transporters (9,15,23,33,42,48,54). However, data concerning the interaction of NNRTIs or NRTIs with efflux transporters are sparse and conflicting (7, 9, 13, 46, 49, 50, 57).…”

mentioning

confidence: 99%

Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation

Bousquet

Pruvost

Guyot

et al. 2009

Antimicrob Agents Chemother

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(multidrug resistance-associated protein), and OAT (organic anion transporter) expression in response to the treatments was quantified by semiquantitative real-time PCR. Cells treated with a double combination (FTC-TFV or TFV-EFV) or the triple combination (FTC-TFV-EFV) produced higher FTC and TFV intracellular concentrations than cells treated with FTC orTFV alone. However, no change in the EFV intracellular concentration was observed. FTC tended to induce abcc5 mRNA expression and EFV tended to induce abcc1 and abcc6 mRNA expression, whereas TFV tended to reduce mdr1, abcc1, abcc5, and abcc6 mRNA expression. Under these conditions, a decrease in the functionality of ABCC was observed, and this decrease was associated with the direct inhibitory actions of these drugs. This in vitro study reveals a benefit of the combination FTC-TFV-EFV in terms of the intracellular FTC and TFV concentrations and highlights the pharmacological mechanisms that lead to this effect.

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Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell line

Cited by 123 publications

References 45 publications

Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir

Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir

Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System

Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation

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