Gene–gene interactions between DRD3, MRP4 and CYP2B6 polymorphisms and its influence on the pharmacokinetic parameters of efavirenz in HIV infected patients

Sánchez-Martín, Almudena; Figueroa, Salvador Cabrera; Cruz, Raquel; Porras-Hurtado, Liliana; Calvo-Boyero, F.; Rasool, Mahmood; Bustos, Cecilia; Cordero, Miguel; Fuertes, Antonio B.; Iglesias, Alejandro Villamor; Luna, Guillermo; Valverde, María P.; Hurlé, Alfonso Domínguez-Gil; Carracedo, Ángel

doi:10.1016/j.dmpk.2016.06.001

Cited by 12 publications

(14 citation statements)

References 37 publications

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“…The reason for this is that although a synonymous variant has no impact on the primary structure, there is a formal possibility that the polymorphism affects the secondary structure of the mRNA by altering its stability and/or translatability, thus resulting to a diversity in protein expression levels [40]. Consistent with results reported in the literature, individuals with rs1751034 TC genotype in ABCC4 had a lower plasma concentration and exposure of oral compounds than those with TT genotype [39]. The other three mutation sites (rs1189437, rs1151471, and rs4148546) belong to intron variants, and there have been no published studies on the association between drug pharmacokinetics and any of them, as far as we know.…”

Section: Discussionsupporting

confidence: 82%

“…Among the variants in the MRP4 gene, two SNPs (rs1751034 and rs1189437) had good correlations with the C max and AUC last of both CK and 20(S)-PPD, as well as their ratio. Although the rs1751034 T>C polymorphism is a synonymous variant, Sanchez-Martin et al showed a significant difference between the ABCC4 rs1751034 T>C polymorphism and the pharmacokinetics of a nonnucleoside reverse transcriptase inhibitor, efavirenz [39]. The reason for this is that although a synonymous variant has no impact on the primary structure, there is a formal possibility that the polymorphism affects the secondary structure of the mRNA by altering its stability and/or translatability, thus resulting to a diversity in protein expression levels [40].…”

Section: Discussionmentioning

confidence: 99%

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Impact of NR1I2, adenosine triphosphate–binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

Zhou

Chen

Wang

et al. 2019

Journal of Ginseng Research

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Background Ginsenoside compound K (CK) is a promising drug candidate for rheumatoid arthritis. This study examined the impact of polymorphisms in NR1I2 , adenosine triphosphate–binding cassette (ABC) transporter genes on the pharmacokinetics of CK in healthy Chinese individuals. Methods Forty-two targeted variants in seven genes were genotyped in 54 participants using Sequenom MassARRAY system to investigate their association with major pharmacokinetic parameters of CK and its metabolite 20(S)-protopanaxadiol (PPD). Subsequently, molecular docking was simulated using the AutoDock Vina program. Results ABCC4 rs1751034 TT and rs1189437 TT were associated with increased exposure of CK and decreased exposure of 20(S)-PPD, whereas CFTR rs4148688 heterozygous carriers had the lowest maximum concentration (C max ) of CK. The area under the curve from zero to the time of the last quantifiable concentration (AUC last ) of CK was decreased in NR1I2 rs1464602 and rs2472682 homozygous carriers, while C max was significantly reduced only in rs2472682. ABCC4 rs1151471 and CFTR rs2283054 influenced the pharmacokinetics of 20(S)-PPD. In addition, several variations in ABCC2 , ABCC4 , CFTR , and NR1I2 had minor effects on the pharmacokinetics of CK. Quality of the best homology model of multidrug resistance protein 4 (MRP4) was assessed, and the ligand interaction plot showed the mode of interaction of CK with different MRP4 residues. Conlusion ABCC4 rs1751034 and rs1189437 affected the pharmacokinetics of both CK and 20(S)-PPD. NR1I2 rs1464602 and rs2472682 were only associated with the pharmacokinetics of CK. Thus, these hereditary variances could partly explain the interindividual differences in the pharmacokinetics of CK.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Impact of NR1I2, adenosine triphosphate–binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

Zhou

Chen

Wang

et al. 2019

Journal of Ginseng Research

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“…10,29,30 ABCC4 polymorphisms (rs1751034 and rs2274407) have been associated with lower and higher maximum plasma efavirenz concentrations, respectively, and ABCG2 rs2231142 has been associated with an increased risk of abnormal dreams with efavirenz. 31,32 Africans are the most genetically diverse population worldwide. 33 South Africa has the world's largest ART programme, with most patients currently receiving efavirenz/tenofovir/emtricitabine.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites

Decloedt

Sinxadi

Zyl

et al. 2018

Journal of Antimicrobial Chemotherapy

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Background: There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. Objectives: We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. Methods: We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. Results: We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log 10-transformed concentrations of plasma efavirenz (b " 0.38, P " 2.7%10 #03), plasma 7hydroxy-efavirenz (b " 0.59, P " 3.7%10 #03), plasma 8-hydroxy-efavirenz:efavirenz ratio (b " #0.31, P " 1.8%10 #04) and CSF efavirenz (b " 0.36, P " 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (b " #0.55, P " 3.5%10 #05), ABCB1 rs115780656 (b " #0.65, P " 4.1%10 #05) and CYP2A6 #48A!C (b " #0.59, P " 0.01). CYP2A6 #48A!C was independently associated with higher CSF 8-hydroxyefavirenz:efavirenz ratio (b " 0.54, P " 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P , 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. Conclusions: We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.

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“… 9 Increased CYP2B6 (or other hepatic enzyme) activity would explain lower systemic efavirenz exposure with increasing estradiol concentrations. Similarly, efavirenz is a substrate for efflux drug transporter MRP4, 10 , 11 which like CYP2B6 may also be induced by estradiol. Increased expression of efflux drug transporter in the gut epithelium may point to decreased efavirenz absorption and is consistent with our findings of lower efavirenz concentrations with increased estradiol.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Hormones and Antiretroviral Exposure in Plasma, Cervicovaginal Fluid, and Upper-Layer Packed Cells of Malawian Women Living with HIV

Nicol

Cottrell

Corbett

et al. 2020

AIDS Research and Human Retroviruses

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Overlap in metabolism pathways of endogenous female sex hormones and antiretroviral drugs may lead to altered exposure to these compounds. In a family planning clinic in Lilongwe, Malawi, blood, blood cell, and cervicovaginal fluid (CVF) samples from seventy-three HIV positive Malawian women taken in follicular and luteal menstrual phases were assessed for estradiol and progesterone by chemiluminescent immunoassay, and for antiretroviral concentration by liquid chromatography-mass spectrometry. In both follicular and luteal phases, estradiol concentrations were lower in women receiving efavirenz compared with women on non-efavirenz regimens or no antiretroviral therapy ( p < .01). Serum estradiol was moderately and negatively correlated with efavirenz plasma ( r = −0.36, p < .001) and CVF ( r = −0.50, p < .001) concentrations. Serum estradiol was a significant predictor of efavirenz CVF concentrations even after adjusting for efavirenz plasma concentrations ( p = .02). In upper-layer packed cells (ULPCs), tenofovir diphosphate (TFVdp) concentrations were similar between follicular and luteal phases and were not correlated with estradiol or progesterone concentrations. Tenofovir concentrations in CVF were not associated with menstrual cycle or serum hormone concentrations. In CVF and plasma, efavirenz concentrations were negatively correlated with serum estradiol concentrations, suggesting a modulatory effect of estradiol on efavirenz metabolism and/or transport processes, and/or an effect of efavirenz on the metabolism of estradiol. Differences in CVF persisted even after adjusting for plasma concentrations, suggesting a mechanism specific to the female genital compartment separate from absorption or hepatic metabolism. In contrast, TFVdp concentrations in ULPC were not influenced by endogenous estradiol or progesterone concentrations.

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Gene–gene interactions between DRD3, MRP4 and CYP2B6 polymorphisms and its influence on the pharmacokinetic parameters of efavirenz in HIV infected patients

Cited by 12 publications

References 37 publications

Impact of NR1I2, adenosine triphosphate–binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

Impact of NR1I2, adenosine triphosphate–binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites

Endogenous Hormones and Antiretroviral Exposure in Plasma, Cervicovaginal Fluid, and Upper-Layer Packed Cells of Malawian Women Living with HIV

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