Genetic Variations in ABCB1 and CYP3A5 as well as Sex Influence Quinine Disposition Among Ugandans

Mukonzo, Jackson; Waako, Paul; Ogwal-Okeng, Jasper; Gustafsson, Lars L.; Aklillu, Eleni

doi:10.1097/ftd.0b013e3181da79d6

Cited by 20 publications

(15 citation statements)

References 38 publications

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“…This observation is in line with previous reports that demonstrate the importance of CYP3A5 genotype for antimalarial drug exposure. 45,46 The finding of significant effect of EFV, but not NVP, on plasma lumefantrine exposure might be because of differences in the extent of CYP3A induction by the two drugs. CYP3A4 and CYP2B6 induction by EFV and NVP is mediated via human nuclear pregnane X receptor and the human constitutive androstane receptor, respectively.…”

Section: Discussionmentioning

confidence: 92%

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

et al. 2015

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We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

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Section: Discussionmentioning

confidence: 92%

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

et al. 2015

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“…Considerable intra-African population structuring at the CYP3A5 gene suggests that there are likely to be multiple pharmacogenetics profiles for key drugs used across the continent, including many used in the treatment and control of malaria [53] and HIV-1 [54]. We identified significant differences between Ethiopians and other sub-Saharan African populations, and intra-Ethiopian diversity, at the CYP3A5 gene.…”

Section: Discussionmentioning

confidence: 99%

Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa

et al. 2013

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BackgroundCytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago.ResultsWe estimate that ~43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A5*3 as ~76,400 years and CYP3A5*6 as ~218,400 years. Finally we report that global CYP3A5 expression levels correlated significantly with aridity measures for 10,000 [Spearmann’s Rho= −0.465, p=0.004] and 50,000 years ago [Spearmann’s Rho= −0.379, p=0.02].ConclusionsSignificant intra-African diversity at the CYP3A5 gene is likely to contribute to multiple pharmacogenetic profiles across the continent. Significant correlations between CYP3A5 expression phenotypes and aridity data are consistent with a hypothesis that the enzyme is important in salt-retention adaptation.

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“…This transporter has been shown to transport quinine (Pussard et al, 2007;Mukonzo et al, 2010) and may play a role in transport of other antimalarial drugs as discussed earlier. In maternal liver, mRNA levels of Abcb1b but not Abcb1a were increased; however, protein levels of MDR1 were unchanged.…”

Section: Discussionmentioning

confidence: 99%

“…Their importance in determining fetal xenobiotic exposure has been well established in vivo in knockout mouse and ex vivo in human placental perfusion models (Vahakangas and Myllynen, 2009;Aye and Keelan, 2013). With regards to therapeutics, MDR1 (P-glycoprotein, ABCB1) plays an important role in the pharmacokinetics of quinine (Pussard et al, 2007;Mukonzo et al, 2010) and could transport other antimalarials, because the Mdr homolog of Plasmodium falciparum, PfMDR1, has been shown to extrude a wide variety of antimalarials including amodiaquine, mefloquine, lumefantrine, and artemisinin, thereby contributing to drug resistance (Foote et al, 1989;Wilson et al, 1989;Price et al, 2004;Sisowath et al, 2007;Sa et al, 2009;Chavchich et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

et al. 2013

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Preventing and treating malaria in pregnancy is a global health priority. However little is known regarding the impact of malaria infection on the maternal and fetal disposition of pharmaceuticals and other xenobiotics. Our objective was to characterize expression of key determinants of drug-disposition in maternal and fetal tissues in a validated murine model of experimental placental malaria. Balb/c mice were infected with Plasmodium berghei at mid gestation [gestational day (GD) 13] and maternal, placental, and fetal tissues were collected at GD19. Expression of key ABC drug transporters and Cyp3a11 was examined by quantitative polymerase chain reaction. Western blotting was used to examine the protein expression of multidrug resistance protein 1 (MDR1, ABCB1). Compared with controls, placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the malaria-infected group (P < 0.05), as was placental MDR1 protein (P < 0.05). Significantly decreased hepatic expression of Abcc2, Abcg2, and Abcb11 and significantly increased expression of Abcb1b, Abcc1, and Abcc3 were seen in malaria-infected dams (P < 0.05) in comparison with uninfected controls. The expression of Abcb1a and Abcg2 was significantly decreased in fetal liver of infected dams, whereas levels of Abcb1b were increased (P < 0.05). Maternal and fetal hepatic expression of Cyp3a11 was significantly downregulated in the malaria group (P < 0.05). Together, malaria-induced alterations in the expression of transporters and drug-metabolizing enzymes in maternal and fetal tissues may alter the disposition of endogenous and therapeutic substrates, potentially impacting maternal and fetal outcomes.

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Genetic Variations in ABCB1 and CYP3A5 as well as Sex Influence Quinine Disposition Among Ugandans

Cited by 20 publications

References 38 publications

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

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