Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein

Storch, Caroline Henrike; Theile, Dirk; Lindenmaier, Heike; Haefeli, Walter E.; Weiß, Johanna

doi:10.1016/j.bcp.2007.01.027

Cited by 141 publications

(119 citation statements)

References 52 publications

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“…22,23 Because malaria and HIV share a wide overlap in their socio-economic and geographical areas of occurrence, many locales with a high malaria burden also have a high HIV burden. Thus, co-administration of antimalarials with antiretroviral drugs is common.…”

Section: Discussionmentioning

confidence: 99%

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Oga

Sekine²,

Shitara³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 μM) and quinidine (1 μM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-toapical (B-A) P-gp-mediated DIG transport at concentrations of 100 μM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general.

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Section: Discussionmentioning

confidence: 99%

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Oga

Sekine²,

Shitara³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…The assay was conducted and validated as described previously [19,23]. Each experiment was performed in duplicate on different days.…”

Section: Impact Of Oxaliplatin Metabolites On Pgp Activity (Calcein Umentioning

confidence: 99%

Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy

Theile

Grebhardt

Haefeli

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.

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“…The reduction in TFV C min and AUC was less during the TDF 1 FPV/RTV period relative to the TDF 1 unboosted FPV period, possibly because the P-gpinhibitory effect of RTV may have partially counteracted the P-gp-induction effect of APV. TPV and NFV also induce intestinal P-gp [36,37], while ATV and LPV markedly inhibit P-gp [38], contributing to their TFV exposureelevating effects.It is unclear why TDF coadministration would increase APV concentrations, as TDF does not affect cytochrome P450 3A4 (CYP3A4) metabolism [9], the primary metabolic pathway for APV, nor does it affect P-gp [39,40], for which APV is a substrate. The increase in APV plasma concentrations during TDF coadministration is in contrast to the reduction in ATV and LPV concentrations seen when unboosted ATV, ATV/RTV or LPV/RTV is given with TDF [13,26,28], which is postulated to occur because of a physicochemical reaction these PIs have with TDF at the time of their absorption in the intestine [11].…”

mentioning

confidence: 99%

Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

et al. 2010

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ObjectiveAn open-label, three-period pharmacokinetic study was conducted to investigate the drug interaction potential between fosamprenavir (FPV) and tenofovir disoproxil fumarate (TDF). MethodsThirty-six healthy subjects received TDF 300 mg once daily (qd) for 7 days (period 1), and then were randomized to 14 days of either FPV 1400 mg twice daily (bid) or FPV/ritonavir (RTV) 700/100 mg bid alone or with TDF (period 2). Subjects continued their randomized dose of FPV for 14 more days, adding or removing TDF based upon its receipt in period 2 (period 3). Twenty-four-hour pharmacokinetic sampling was carried out on day 7 of period 1 and on day 14 of periods 2 and 3. Steady-state plasma amprenavir (APV) and tenofovir (TFV) pharmacokinetics were assessed by noncompartmental analysis and parameter values observed with each regimen were compared using geometric mean ratios with 90% confidence intervals. ResultsAfter TDF coadministration, APV geometric mean minimum concentration (C min ), maximum concentration (C max ), and area under the plasma concentration-time curve (AUC) increased by 31, 3 and 7% above values observed with unboosted FPV alone; they also increased by 31, 4 and 16% above values observed with FPV/RTV alone. TFV C min , C max and AUC decreased by 12, 25 and 15% after FPV coadministration and by 9, 18 and 7% after FPV/RTV coadministration. No significant changes in RTV pharmacokinetics were observed. No differences were noted in adverse events among dosing periods. ConclusionsIn this evaluation of the interaction between FPV and TDF, increases in APV exposures and modest decreases in TFV exposures were observed. These were unlikely to be clinically significant.Keywords: drug interaction, fosamprenavir, tenofovir IntroductionTenofovir disoproxil fumarate (TDF), the prodrug for the nucleotide reverse transcriptase inhibitor tenofovir (TFV), has proved highly effective in the treatment of antiretroviralnaïve and antiretroviral-experienced HIV-infected patients when combined in regimens containing nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) [1][2][3][4][5][6][7][8]. At the time at which TDF was developed, TDF-PI drug-drug interactions were not expected because TFV is eliminated renally by glomerular filtration and active tubular secretion, whereas PIs are hepatically metabolized [9]. However, drug interaction studies showed that the area under the plasma concentration-time curve (AUC; exposure) DOI: 10.1111DOI: 10. /j.1468DOI: 10. -1293DOI: 10. .2009 (2010), 11, 193-199 193 for TFV increased by 22-32% when TDF was combined with unboosted atazanavir (ATV), ATV boosted by ritonavir (ATV/ RTV), lopinavir (LPV)/RTV, or darunavir (DRV)/RTV, accompanied by 15-20% decreases in ATV and LPV AUCs and a 21% increase in the DRV AUC [10][11][12][13][14]. Although the combination of TDF with fosamprenavir (FPV), the phosphate ester prodrug of the PI amprenavir (APV), has been reported to be effective and well tolerated in HIV-infected patients [4,[15][16][17][18][19], a fo...

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Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein

Cited by 141 publications

References 52 publications

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy

Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

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