Review
The complexities of antiretroviral drug–drug interactions: role of ABC and SLC transporters

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Treatment of human immunodeficiency virus (HIV) infection involves a combination of several antiviral agents belonging to different pharmacological classes. This combination is referred to as highly active antiretroviral therapy (HAART). This treatment has proved to be very effective in suppressing HIV replication, but antiretroviral drugs have complex pharmacokinetic properties involving extensive drug metabolism and transport by membrane-associated drug carriers. Combination drug therapy often introduces complex drug–drug interactions that can result in toxic or sub-therapeutic drug concentrations, compromising treatment. This review focuses on the role of ATP-binding cassette (ABC) membrane-associated efflux transporters and solute carrier (SLC) uptake transporters in antiretroviral drug disposition, and identifies clinically important antiretroviral drug–drug interactions associated with changes in drug transport.

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.

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