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MDR- and CYP3A4-Mediated Drug–Drug Interactions

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Abstract

P-glycoprotein (P-gp), multiple drug resistance associated proteins (MRPs), and cytochrome P450 3A4 together constitute a highly efficient barrier for many orally absorbed drugs. Multidrug regimens and corresponding drug–drug interactions are known to cause many adverse drug reactions and treatment failures. Available literature, clinical reports, and in vitro studies from our laboratory indicate that many drugs are substrates for both P-gp and CYP3A4. Our primary hypothesis is that transport and metabolism of protease inhibitors (PIs) and NNRTIs will be altered when administered in combination with azole antifungals, macrolide, fluroquinolone antibiotics, statins, cardiovascular agents, immune modulators, and recreational drugs [benzodiazepines, cocaine, lysergic acid dithylamide (LSD), marijuana, amphetamine (Meth), 3,4-methylenedioxymethamphetamine (MDMA), and opiates] due to efflux, and/or metabolism at cellular targets. Therefore, such drug combinations could be a reason for the unexpected and unexplainable therapeutic outcomes. A number of clinical reports on drug interaction between PIs and other classes (macrolide antibiotics, azole antifungals, cholesterol lowering statins, cardiovascular medicines, and immunomodulators) are discussed in this article. MDCKII-MDR1 was employed as an in vitro model to evaluate the effects of antiretrovirals, azole antifungals, macrolide, and fluroquinolone antibiotics on efflux transporters. Ketoconazole (50 μM) enhanced the intracellular concentration of 3H ritonavir. The inhibitory effects of ketoconazole and MK 571 on the efflux of 3H ritonavir were comparable. An additive effect was observed with simultaneous incorporation of ketoconazole and MK 571. Results of 3H ritonavir uptake studies were confirmed with transcellular transport studies. Several fluroquinolones were also evaluated on P-gp-mediated efflux of 3H cyclosporin and 14C erythromycin. These in vitro studies indicate that grepafloxacin, levofloxacin, and sparfloxacin are potent inhibitors of P-gp-mediated efflux of 14C erythromycin and 3H cyclosporin. Simultaneous administration of fluoroquinolones and macrolides could minimize the efflux and metabolism of both of the drugs. Effects of erythromycin and ketoconazole on carbamazepine metabolism were examined. Formation of 10,11-epoxy carbamazepine, a major CBZ metabolite, was significantly inhibited by these agents. Therefore, drug efflux proteins (P-gp, MRPs) and metabolizing enzyme (CYP450) are major factors in drug interactions. Overlapping substrate specificities of these proteins result in complex and sometimes perplexing pharmacokinetic profiles of multidrug regimens. Drug–drug interactions with PIs and other coadministered agents for human immunodeficiency virus (HIV) positive population have been discussed in light of efflux transporters and metabolizing enzymes. This article provides an insight into low and variable oral bioavailability and related complications leading to loss of therapeutic activity of MDR and CYP 450 substrates.

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Abbreviations

ABC:

ATP binding cassette

AF:

activation function

AIDS:

acquired immunodeficiency syndrome

AUC:

areas under curves

BCRP:

breast cancer resistance protein

BSEP:

bile salt export pump

CAR:

constitutive androstane receptor

CYP:

cytochrome P450

GHB:

gamma hydroxybutyrate

GSTs:

glutathione-S-transferases

HAAT:

highly active antiretroviral therapy

HIV:

human immunodeficiency virus

LBD:

ligand binding domain

LSD:

lysergic acid dithylamide

Meth:

amphetamine

MDR:

multidrug resistance

MDMA:

3,4-methylenedioxymethamphetamine

MRPs:

multiple drug resistance associated proteins

NRTIs:

nucleoside and nucleotide reverse transcriptase inhibitors

NNRTIs:

nonnucleoside reverse transcriptase inhibitors

OIs:

opportunistic infections

PIs:

protease inhibitors

P-gp:

P-glycoprotein

PXR:

pregnane X receptor

RXR:

retinoid X receptor

UGT:

uridine 5′-diphosphate glucuronosyltransferase

VRD:

vitamin D response

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Acknowledgements

The authors would like to acknowledge Jignesh Patel, Vineet Sikri, and Balasubrahmanyam Budda for their contribution in in vitro data. This study was supported by NIH grants RO1 EY 09171-12, RO1 EY 10659-10, and RO1 GM 64320-03.

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  1. Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri–Kansas City, 5005 Rockhill Road, Kansas City, MO, 64110-2499, USA

    Dhananjay Pal & Ashim K. Mitra

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  1. Dhananjay Pal
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  2. Ashim K. Mitra
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Correspondence to Ashim K. Mitra.

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Pal, D., Mitra, A.K. MDR- and CYP3A4-Mediated Drug–Drug Interactions. Jrnl Neuroimmune Pharm 1, 323–339 (2006). https://doi.org/10.1007/s11481-006-9034-2

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  • DOI: https://doi.org/10.1007/s11481-006-9034-2

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