Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory

Varshney, Ekta; Saha, Nilanjan; Tandon, Monika; Shrivastava, Vikesh; Ali, Shakir

doi:10.1186/2193-1801-1-34

Cited by 19 publications

(16 citation statements)

References 38 publications

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“…SNPs at exon 4 (516 G > T) and exon 7 (983 T > C) of CYP2B6 are known to reduce the catalytic activity of enzyme resulting in higher trough plasma drug levels [ 41 , 43 ] suggesting that lead in dosing could be more appropriate for a 516TT or 983CC genotype individual. In view of the finding by Varshney et al that approximately 20% of the Indian population are poor drug metabolizers [ 44 ], there is an increased likelihood of a rapid metabolizer genotype 516 GG or GT in our cohort which might have confounded our results. Nevertheless, this is the first longitudinal study in India that assessed nevirapine concentration in children during the dose escalation period at ART initiation, thus contributing important information on nevirapine pharmacokinetics in children.…”

Section: Discussionmentioning

confidence: 82%

Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring

et al. 2017

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Nevirapine, a component of antiretroviral therapy (ART) in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 (‘lead-in period’), and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high performance liquid chromatography (HPLC) at days 7, 14 (lead-in period) and 28 (full dose period) after ART initiation amongst HIV-1 infected children initiating nevirapine-based ART in southern India. Among the 20 children (50% male, median age 9 years) included in the study, sub-therapeutic trough plasma nevirapine concentration (<4μg/ml) was seen in 65% (13/20) of children during the lead-in period within two weeks of ART initiation and among 10% of children at 4 weeks during full-dose nevirapine. Adherence was documented as ≥95% in all children by both caregiver self-report and pill count. Median nevirapine concentrations achieved at week 1 was 4.8 μg/ml, significantly lower than 8 μg/ml, the concentration achieved at week 4 (p = 0.034). Virological failure at one year of ART was observed in six children, and was not associated with median nevirapine concentration achieved during week 1, 2 or 4. We conclude that the dose escalation strategy currently practiced among young children living with HIV-1 resulted in significant subtherapeutic nevirapine concentration (≤4μg/ml) during the lead-in period. We call for a closer look at pediatric-focused dosing strategies for nevirapine initiation in young children. Further studies to establish age-appropriate threshold nevirapine concentration are warranted in young children to corroborate the role of therapeutic drug monitoring in predicting virological outcome.

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Section: Discussionmentioning

confidence: 82%

Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring

et al. 2017

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“…A bimodal frequency distribution of urinary NAT2 metabolic ratio was observed (SW-W = 0.93, p < 0.0001), and ranged from 0.003 to 0.743 (median 0.025; IQR 0.013; 0.176). Probit plot and regression analysis was used to identify the anti-mode cut-off value to classify slow and rapid acetylators as described previously [ 44 , 45 ]. Using an anti-mode value of 0.1 as a cutoff, which was common for both study populations, 70% of the subjects were classified as phenotypically slow acetylators.…”

Section: Resultsmentioning

confidence: 99%

N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians

Aklillu

Carrillo

Makonnen

et al. 2018

Eur J Clin Pharmacol

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Background and objectivesN-acetyltransferase 2 (NAT2) metabolize several drugs including isoniazid. We investigated the effect of genotype, geographical difference, and smoking habit on NAT2 phenotype in Ethiopians.MethodsGenotyping for NAT2 191G > A, 341 T > C, 590G > A, and 857G > A was performed in 163 unrelated healthy Ethiopians (85 living in Ethiopia and 78 living in Sweden). The NAT2 phenotype was determined using caffeine as a probe and log AFMU/(AFMU + 1X + 1 U) urinary metabolic ratio (MR) as an index.ResultsThe frequencies of NAT2*4, *5, *6, *7, and *14 haplotypes were 14.1, 48.5, 30.1, 5.5, and 1.8%, respectively. The frequencies of rapid (NAT2*4/*4), intermediate (heterozygous *4), and slow (no *4 allele) acetylator genotypes were 1.8, 24.6, and 73.6%, respectively. The distribution NAT2 MR was bimodal with 70% being phenotypically slow acetylators. NAT2 genotype (p < 0.0001) and country of residence (p = 0.004) independently predicted NAT2 phenotype. Controlling for the effect of genotype, ethnic Ethiopians living in Ethiopia had significantly higher NAT2 MR than those living in Sweden (p = 0.006). NAT2 genotype-phenotype concordance rate was 75%. Distinct country-of-residence-based genotype-phenotype discordance was observed. The proportion of phenotypically determined rapid acetylators was significantly higher and slow acetylators was lower in Ethiopians living in Ethiopia (39% rapid, 61% slow) than in Sweden (20% rapid, 80% slow). Sex and smoking had no significant effect on NAT2 MR.ConclusionsWe report a high prevalence of NAT 2 slow acetylators in Ethiopians and a conditional NAT2 genotype-phenotype discordance implicating a partial phenotype conversion and metabolic adaptation. Gene-environment interactions regulate NAT2 phenotype.

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“…Resent advances in the understanding of this enzyme have made it a potential therapeutic target. 151,152 Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory http://www.ncbi.nlm.nih.gov/pubmed/23961363 153 "Identification of poor and rapid metabolizers for the category of drugs metabolized by cytochrome P450 2B6 (CYP2B6) is important for understanding the differences in clinical responses of drugs metabolized by this enzyme... Results indicate that 20.56% individuals in the target population were poor metabolizers for the category of drugs metabolized by CYP2B6.…”

Section: Impact Of Cyp1a2 and Cyp2d6 Polymorphisms On Drug Metabolismmentioning

confidence: 99%

Polymorphisms in Serotonergic Pathways Influence the Outcome of Antidepressant Therapy in Psychiatric Inpatients

Staeker

Leucht

Laika

et al. 2014

Genetic Testing and Molecular Biomarkers

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Serotonergic pathways are known to play an essential role in the effects generated by antidepressants. Polymorphisms in serotonin receptor and transporter genes have been identified as an important factor. To investigate which of these polymorphisms may be useful to predict clinical outcome, we assessed their effect in a naturalistic clinical study. We studied the influence of the 5-hydroxytryptamine transporter (5-HTT) variable number of tandem repeats (VNTR), 5-HTTLPR/rs25531 and a 5-HTR2A intron 2 SNP with regard to response and side effects in 273 psychiatric inpatients. Main clinical assessments included Clinical Global Impressions ratings, paranoid depression scale self-rating scale and Dosage Record, and Treatment Emergent Symptoms (DOTES) Scale. We found significant associations between 5-HTTLPR/rs25531 S/L(G) alleles and response and side effects in 100 patients with selective serotonin reuptake inhibitor (SSRI) treatment (p = 0.037, CGI-I ≤ 2: 0% vs. 19% and p = 0.0005, DOTES cluster c: 0.76 vs. 0.19). 5-HTT VNTR and 5-HTR2A intron 2 polymorphisms were associated significantly with adverse effects in patients with selective and nonselective SRI (5-HTT VNTR 12/12: n = 170, p = 0.0001, side effect rates: 51% vs. 19% and rs7997012 [A/A]: n = 50, p = 0.020, side effects rates: 43% vs. 11%). No impact of the polymorphisms on mirtazapine treatment was found. Our study confirms the influence of serotonergic polymorphisms at the receptor and transporter level on SSRI response and side effects, supporting previous reports based on various study designs. The effects were strong enough to be noticed clinically in this naturalistic setting. However, randomized controlled trials are warranted to provide unequivocal evidence of the clinical usefulness of pretherapeutic screening for these polymorphisms.

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Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory

Cited by 19 publications

References 38 publications

Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring

Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring

N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians

Polymorphisms in Serotonergic Pathways Influence the Outcome of Antidepressant Therapy in Psychiatric Inpatients

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