Trends in Pharmacological Sciences
ReviewThe complexities of antiretroviral drug–drug interactions: role of ABC and SLC transporters
Introduction
Since the discovery of the human immunodeficiency virus (HIV), major progress has been made in the pharmacological treatment of HIV infection. Six mechanistic classes of antiretroviral drugs (Table 1) which suppress different steps of the HIV replication cycle (Fig. 1) are available [1]. The effectiveness of antiretroviral treatment relies on the ability to prevent the development of drug-resistant viral strains and maintain sufficiently high levels of drugs in plasma and tissue to suppress HIV replication. Concurrent administration of three or more antiretroviral drugs from different classes (i.e. highly active antiretroviral therapy (HAART)) has proved to significantly reduce viral load, delay the onset of viral drug resistance, and prolong treatment efficacy [2]. However, many combinations of antiretroviral drugs lead to significant drug–drug interactions, resulting in sub-therapeutic or toxic drug concentrations with a high risk for treatment failure or drug-induced toxicities [3]. Identifying pharmacokinetic and pharmacodynamic mechanisms contributing to these interactions is a major focus of HIV clinical research.
Disposition of antiretroviral drugs involves drug metabolism by cytochrome P450 (CYP) enzymes and drug transport by ATP-binding cassette (ABC) and solute carrier (SLC) transporters 4, 5, 6. Many antiretroviral drug–drug interactions were previously linked to changes in the activity of CYP enzymes. However, it is increasingly recognized that ABC and SLC transporters also have a central role in the disposition of antiretroviral drugs, and can contribute to many drug–drug interactions of clinical importance. Since the involvement of CYPs in antiretroviral drug–drug interactions has been comprehensively reviewed 4, 6, 7, this manuscript will focus on the role of ABC and SLC transporters in the disposition of antiretroviral drugs and drug–drug interactions.
Section snippets
Role of ABC transporters in antiretroviral therapy
The ATP-binding cassette (ABC) superfamily includes several efflux drug transporters such as P-glycoprotein (Pgp, MDR1-gene product), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP, ABCG2) [8]. These primary active efflux pumps can significantly limit the disposition of antiretroviral drugs at several viral target sites. Many of these drugs are substrates, inhibitors and/or inducers of ABC transporters (Table 2), so complex drug–drug interactions can
Role of SLC transporters in antiretroviral therapy
Antiretroviral drugs are known to interact with several SLC families, including organic anion-transporting polypeptides (OATPs), organic anion and organic cation transporters (OATs, OCTs), as well as equilibrative and concentrative nucleoside transporters (ENTs, CNTs) 54, 55, 56, 57.
Clinical implications of antiretroviral drug–drug interactions: role of transporters
Clinical studies have identified many drug–drug interactions involving highly metabolized antiretroviral drugs (i.e. PIs, NNRTIs, maraviroc, and raltegravir). These often result from inhibition or induction of CYP-mediated metabolism by PIs and NNRTIs 3, 4, 6. However, many of these drugs are also potent inhibitors of Pgp (Table 2), particularly ritonavir [25] and lopinavir 26, 27 (Table 2), and some can induce Pgp functional expression after chronic exposure, including amprenavir, ritonavir,
Mechanisms of antiretroviral drug–drug interactions: role of transporters at specific sites
Changes in plasma drug levels are a reflection of complex drug–drug interactions occurring during intestinal absorption, hepatic elimination, and/or renal excretion of drugs. However, antiretroviral penetration into sanctuaries of HIV infection (e.g. lymphocytes, CNS, and genital organs) or across the placenta in pregnant HIV+ women is also a determinant of treatment safety and efficacy. ABC and SLC transporters are highly expressed at these target sites and barriers, so transporter-mediated
Conclusion
Interactions between antiretroviral drugs are very complex and can involve a combination of drug-induced effects, including toxicity, transient and long-term changes in the activity and/or expression of drug transporters and metabolic enzymes, as well as competition for intracellular enzymes required for drug activation. These effects are also highly variable between patients due to genetic differences, age, sex, distinct diet, environmental factors, and health-related factors such as disease
Acknowledgements
This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR), the Ontario HIV Treatment Network (OHTN), Ministry of Health of Ontario and the Canadian Foundation for HIV/AIDS Research (CANFAR) (awarded to Dr. Reina Bendayan). Mr. Gary Chan is a recipient of a Natural Sciences and Engineering Research Council of Canada (NSERC) doctoral scholarship award; Ms. Olena Kis and Mr. Kevin Robillard are recipients of an OHTN doctoral studentship award.
References (114)
Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study
Lancet
(2002)Comparison of the induction of P-glycoprotein activity by nucleotide, nucleoside, and non-nucleoside reverse transcriptase inhibitors
Eur. J. Pharmacol.
(2008)Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein
Biochem. Pharmacol.
(2007)Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR
J. Biol. Chem.
(2001)Emtricitabine: inhibitor and substrate of multidrug resistance associated protein
Eur. J. Pharm. Sci.
(2008)Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein
Biochem. Pharmacol.
(2004)Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia
Chem. Biol. Interact.
(2004)Multi-level analysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination
J. Biol. Chem.
(2008)Electrogenic uptake of nucleosides and nucleoside-derived drugs by the human nucleoside transporter 1 (hCNT1) expressed in Xenopus laevis oocytes
FEBS Lett.
(2000)Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib)
J. Biol. Chem.
(2001)
Influx mechanism of 2′,3′-dideoxyinosine and uridine at the blood-placenta barrier
Placenta
The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research
Antiviral Res.
Antiretroviral drugs
J. Clin. Pharmacol.
An update and review of antiretroviral therapy
Pharmacotherapy
The role of cytochrome P450 in antiretroviral drug interactions
Expert. Opin. Drug Metab. Toxicol.
Drug transporters in HIV Therapy
Top. HIV. Med.
Drug interactions with new and investigational antiretrovirals
Clin. Pharmacokinet.
Transporters and drug therapy: implications for drug disposition and disease
Clin. Pharmacol. Ther.
HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter
Biochemistry
The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors
J. Clin. Invest.
Involvement of P-glycoprotein in the transport of saquinavir and indinavir in rat brain microvessel endothelial and microglia cell lines
Pharm. Res.
Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport
AIDS
Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line
J. Neurosci. Res.
P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines
Biol. Pharm. Bull.
Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid
Drug Metab. Dispos.
Intestinal absorption enhancement of the ester prodrug tenofovir disoproxil fumarate through modulation of the biochemical barrier by defined ester mixtures
Drug Metab. Dispos.
P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution
Drug Metab. Dispos.
Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV
Drug Metab. Dispos.
Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme
Drug Metab. Dispos.
Overview of the pharmacogenetics of HIV therapy
Pharmacogenomics. J.
Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro
Drug Metab. Dispos.
Etravirine for the treatment of HIV infection
Expert Rev. Anti. Infect. Ther.
Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir
J. Clin. Pharmacol.
Lopinavir: acute exposure inhibits P-glycoprotein; extended exposure induces P-glycoprotein
AIDS
Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions
Drug Metab. Dispos.
Induction of P-glycoprotein expression by HIV protease inhibitors in cell culture
AIDS
Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood-brain barrier
AIDS Res. Hum. Retroviruses
Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in rats
Xenobiotica
Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors
Drug Metab. Dispos.
Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers
Antimicrob. Agents Chemother.
Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood--brain barrier
AIDS
Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes
J. Antimicrob. Chemother.
Modulation of the intracellular accumulation of saquinavir in peripheral blood mononuclear cells by inhibitors of MRP1, MRP2, P-gp and BCRP
AIDS
Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs
AIDS
Multidrug resistance protein 1-mediated transport of saquinavir by microglia
Neuroreport
Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study
J. Acquir. Immune. Defic. Syndr.
Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5
Mol. Pharmacol.
Cited by (198)
Nanomedicines encountering HIV dementia: A guiding star for neurotherapeutics
2022, Journal of Drug Delivery Science and TechnologyInterference between copper transport systems and platinum drugs
2021, Seminars in Cancer BiologyHIV in pregnancy: Mother-to-child transmission, pharmacotherapy, and toxicity
2021, Biochimica et Biophysica Acta - Molecular Basis of DiseaseNovel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection: Microbiologic perspectives and anatomic considerations for sanctuary sites
2021, Journal of Infection and Public Health