Potential of novel antiretrovirals to modulate expression and function of drug transporters in vitro

Zembruski, Nadine Cécile Luise; Büchel, Gabriele; Jödicke, Lisa; Herzog, Melanie; Haefeli, Walter E.; Weiß, Johanna

doi:10.1093/jac/dkq501

Cited by 62 publications

(54 citation statements)

References 55 publications

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“…Tissue inflammation and cytokine secretion are known to alter functional expression of drug transporters and CYP enzymes in other disease states (e.g., inflammatory bowel syndrome) (21). Furthermore, we and other investigators have previously reported that the functional expression of drug transporters in brain parenchyma, blood-brain and bloodtestis barriers, and sigmoid colon epithelium is altered by the HIV antigens, viral infection-associated inflammation, and ARVs (22)(23)(24)(25)(26)(27)(28). The main objective of this study was to investigate the impact of HIV-1 infection and suppressive ART on the expression of intestinal drug transporters and metabolic enzymes in the intestinal mucosa of HIV-infected subjects.…”

mentioning

confidence: 85%

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Kis

Sankaran-Walters

Hoque

et al. 2016

Antimicrob Agents Chemother

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؉ ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV ؉ naive group than in the control group and was partially restored to baseline levels in HIV ؉ subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV ؉ subjects on ART relative to HIV ؉ ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV ؉ subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV ؉ subjects. This has clinical implications when using data from healthy volunteers to guide ART.

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mentioning

confidence: 85%

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Kis

Sankaran-Walters

Hoque

et al. 2016

Antimicrob Agents Chemother

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“…29 Preliminary data suggest that raltegravir may be affected by P-glycoprotein, although clinically significant interactions via this mechanism have not been well defined. 30 In contrast, the investigational integrase inhibitor elvitegravir, which is in late-stage development, is a CYP3A4 substrate and requires boosting with an inhibitor to achieve therapeutic concentrations. 31 Pharmacodynamic interactions may affect the efficacy or toxicity of a drug in an additive, synergistic, or antagonistic manner.…”

Section: Management Of Drug Interactionsmentioning

confidence: 99%

Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines

Tseng

Foisy

Hughes

et al. 2012

CJHP

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“…Management of DDIs in HIV subjects is challenging, because the major mechanisms of DDIs in antiretroviral combination therapy involve cytochrome P450 (P450) enzymes, ATP-binding cassette efflux transporters, and solute carrier uptake transporters (Zembruski et al, 2011a). Most PIs (e.g., lopinavir, fosamprenavir, darunavir) are substrates or inhibitors of CYP3A4, and many of these agents require boosting with ritonavir, a very potent CYP3A4 inhibitor (Hull and Montaner, 2011).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

et al. 2012

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Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC 50 values > 30 mM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC 50 = 1.9 mM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.

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Potential of novel antiretrovirals to modulate expression and function of drug transporters in vitro

Abstract: The new antiretrovirals bear the potential to modulate expression and function of several ABC transporters, with elvitegravir revealing the highest interaction potential.

Cited by 62 publications

References 55 publications

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines

In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

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