Differences in nevirapine biotransformation as a factor for its sex-dependent dimorphic profile of adverse drug reactions

Marinho, Aline T.; Rodrigues, Patrícia; Caixas, Umbelina; Antunes, Alexandra M. M.; Branco, Teresa; Harjivan, Shrika G.; Marques, M. Matilde; Monteiro, Emília C.; Pereira, Sofia A.

doi:10.1093/jac/dkt359

Cited by 23 publications

(15 citation statements)

References 64 publications

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“…While some studies report genderrelated differences in terms of virological and immunological response to HAART, others do not (Anderson, 2008;Carr et al, 2014;Dong et al, 2012;Marinho et al, 2013). In this study, we report of an over-representation of females (81%).…”

Section: Demographic Characteristicscontrasting

confidence: 50%

“…2011) 0.31 0.07 N/A Ugandan (Mukonzo et al, 2009) 0.36 0.10 NA Ghanaian (Bains et al, 2013;Griese et al 1999) 0 that it could be due to differential drug biotransformation, fat content, and exogenous and endogenous hormonal expression differences in males and females (Bersoff-Matcha et al, 2001;Dong et al, 2012;Marinho et al, 2013). Expression of liver enzymes responsible for drug metabolism has also been shown to vary with gender and BMI (Antinori et al, 2001;Bersoff-Matcha et al, 2001).…”

Section: Anthropometry Data and Nvp Plasma Concentrationmentioning

confidence: 99%

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Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-toperson variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G ( p < 0.001) and 516G/T ( p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes ( p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count ( p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter-and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.

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Section: Demographic Characteristicscontrasting

confidence: 50%

Section: Anthropometry Data and Nvp Plasma Concentrationmentioning

confidence: 99%

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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“…Upregulation of Gstm3 may have significance in that previous investigators have shown reactive metabolites from SULT activation of 12-hydroxy NVP (Antunes et al 2010) to interact with and form haptens with GSTpi both in vitro and in NVP-treated patient's serum (Meng et al 2013), the suggestion here being that Gstm3 may also be a target for haptan formation and perhaps enzymatic inactivation in this model. There are numerous reports of reactive metabolites derived from NVP (Marinho et al 2014) and as evidenced by gene expression, key routes of reactive metabolite production were clearly dysregulated (Cyp3a4 and Cyp2b6) after NGN treatment, which exhibited fairly similar elevations in treatment with NVP alone. However, Sult1e1 was markedly increased in expression in the NGN group as compared with the NVP-alone group.…”

Section: Discussionmentioning

confidence: 95%

Drug-induced Liver Fibrosis

et al. 2016

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Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVPinduced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/ 100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C.

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“…The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression [4] and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1) increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6].…”

mentioning

confidence: 99%

“…The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12-hydroxy-NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP-induced toxicity.…”

mentioning

confidence: 99%

Sex differences in apolipoprotein A1 and nevirapine‐induced toxicity

Marinho¹,

Dias²,

Antunes³

et al. 2014

Journal of the International AIDS Society

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Nevirapine (NVP) is associated with severe liver and skin toxicity through sulfotransferase (SULT) bioactivation of the phase I metabolite 12-hydroxy-NVP [1–3]. The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression [4] and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1) increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabolism and liver function. The study protocol was firstly approved by the hospitals’ Ethics Committees. All included individuals were HIV-infected patients treated with NVP for at least one month. The plasma concentrations of NVP and its phase I metabolites were quantified by HPLC [7]. ApoA1 levels were assessed by an immunoturbidimetric assay. Forty-nine HIV-infected patients on NVP were included (53% men, 59% Caucasian). NVP plasma levels were correlated with HDL-cholesterol (Spearman r=0.2631; p=0.0441) and ApoA1 (Spearman r=0.3907; p=0.0115). Women had higher ApoA1 levels than men (Student's t Test; p=0.0051). In both sexes, 12-hydroxy-NVP levels were negatively correlated with ApoA1 (male: Spearman r=−0.3810; p=0.0499 female: Spearman r=−0.5944; p=0.0415). In men, ApoA1 was positively correlated with aspartate aminotransferase (AST, Spearman r=0.5507; p=0.0413), while in women ApoA1 was associated (Spearman r=0.6408; p=0.0056) with alanine aminotransferase (ALT). These results show sex differences in NVP-induced ApoA1 synthesis. The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12-hydroxy-NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP-induced toxicity.

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Differences in nevirapine biotransformation as a factor for its sex-dependent dimorphic profile of adverse drug reactions

Cited by 23 publications

References 64 publications

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Drug-induced Liver Fibrosis

Sex differences in apolipoprotein A1 and nevirapine‐induced toxicity

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