Implications of genetic variation of common Drug Metabolizing Enzymes and ABC Transporters among the Pakistani Population

Afsar, Nasir Ali; Bruckmueller, Henrike; Werk, Anneke Nina; Nisar, Muhammad Kashif; Ahmad, Hayat; Cascorbi, Ingolf

doi:10.1038/s41598-019-43736-z

Cited by 19 publications

(13 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The probability of having a CYP2C19 non-NM predicted phenotype due to high frequencies of the non-functional CYP2C19*2 allele and/or the increased function CYP2C19 * 17 allele is highest in India (non-NM probability estimate 80.1%) 56 , 60 , 61 , Pakistan (non-NM probability estimate 74.8%) 55 , 62 , 63 , and Iran (non-NM probability estimate 69.2%) 64 , 65 . The probability is lowest in countries in the Americas, particularly Mexico (non-NM probability estimate 31.7%) 66 – 68 and Costa Rica (non-NM probability estimate 33.9%) 69 .…”

Section: Resultsmentioning

confidence: 99%

Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19

et al. 2021

View full text Add to dashboard Cite

Extensive migration has led to the necessity of knowledge regarding the treatment of migrants with different ethnical backgrounds. This is especially relevant for pharmacological treatment, because of the significant variation between migrant groups in their capacity to metabolize drugs. For psychiatric medications, CYP2D6 and CYP2C19 enzymes are clinically relevant. The aim of this meta-analysis was to analyze studies reporting clinically useful information regarding CYP2D6 and CYP2C19 genotype frequencies, across populations and ethnic groups worldwide. To that end, we conducted a comprehensive meta-analysis using Embase, PubMed, Web of Science, and PsycINFO (>336,000 subjects, 318 reports). A non-normal metabolizer (non-NM) probability estimate was introduced as the equivalent of the sum-prevalence of predicted poor, intermediate, and ultrarapid metabolizer CYP2D6 and CYP2C19 phenotypes. The probability of having a CYP2D6 non-NM predicted phenotype was highest in Algeria (61%) and lowest in Gambia (2.7%) while the probability for CYP2C19 was highest in India (80%) and lowest in countries in the Americas, particularly Mexico (32%). The mean total probability estimates of having a non-NM predicted phenotype worldwide were 36.4% and 61.9% for CYP2D6 and CYP2C19, respectively. We provide detailed tables and world maps summarizing clinically relevant data regarding the prevalence of CYP2D6 and CYP2C19 predicted phenotypes and demonstrating large inter-ethnic differences. Based on the documented probability estimates, pre-emptive pharmacogenetic testing is encouraged for every patient who will undergo therapy with a drug(s) that is metabolized by CYP2D6 and/or CYP2C19 pathways and should be considered in case of treatment resistance or serious side effects.

show abstract

Section: Resultsmentioning

confidence: 99%

Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Previous sequencing of the equine CYP2D50 gene identified several exonic SNPs that may affect enzyme activity and metabolism of CYP2D substrates [11,12]. It is important to note that other factors may influence the metabolism of drugs in vivo, including epigenetic changes, polymorphisms within other genes such as transporters involved in drug absorption [38], age, and environment, such as diet and toxicant exposure [39]. While phenotyping is a valuable tool to assess in vivo metabolism of CYP2D substrates, genotyping horses identified as high-or low-MRs would determine whether observed differences in metabolism arise from altered CYP2D82 activity as opposed to nongenetic or epigenetic differences.…”

Section: Discussionmentioning

confidence: 99%

Functional phenotyping of the CYP2D6 probe drug codeine in the horse

et al. 2021

View full text Add to dashboard Cite

Background In humans, the drug metabolizing enzyme CYP2D6 is highly polymorphic resulting in substantial differences in the metabolism of drugs including anti-arrhythmics, neuroleptics, and opioids. The objective of this study was to phenotype a population of 100 horses from five different breeds and assess differences in the metabolic activity of the equine CYP2D6 homolog using codeine as a probe drug. Administration of a probe drug is a common method used for patient phenotyping in human medicine, whereby the ratio of parent drug to metabolite (metabolic ratio, MR) can be used to compare relative enzyme function between individuals. A single oral dose of codeine (0.6 mg/kg) was administered and plasma concentrations of codeine and its metabolites were determined using liquid chromatography mass spectrometry. The MR of codeine O-demethylation [(codeine)/(morphine + morphine-3-glucuronide + morphine-6-glucuronide)] was determined using the area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-∞) for each analyte and used to group horses into predicted phenotypes (high-, moderate-, and low-MR). Results The MR of codeine O-demethylation ranged from 0.002 to 0.147 (median 0.018) among all horses. No significant difference in MR was observed between breeds, age, or sex. Of the 100 horses, 11 were classified as high-MR, 72 moderate-MR, and 17 low-MR. Codeine AUC0-∞ and O-demethylation MR were significantly different (p < 0.05) between all three groups. The mean ± SD MR was 0.089 ± 0.027, 0.022 ± 0.011, and 0.0095 ± 0.001 for high-, moderate-, and low-MR groups, respectively. The AUC for the morphine metabolites morphine-3-glucuronide and morphine-6-glucuronide were significantly different between high-and low-MR groups (p < 0.004 and p < 0.006). Conclusions The MR calculated from plasma following codeine administration allowed for classification of horses into metabolic phenotypes within a large population. The range of codeine metabolism observed among horses suggests the presence of genetic polymorphisms in CYP2D82 of which codeine is a known substrate. Additional studies including CYP2D82 genotyping of high- and low-MR individuals are necessary to determine the presence of CYP2D polymorphisms and their functional implications with respect to the metabolism of therapeutics.

show abstract

“…Punjabi ethnics have a complex admixture of South Asian, East Asian and West Eurasian lineages, whereas, Pathan, Balochi and Sindhi share alleles with Greeks and Georgians [53][54][55]. While the Urdu speaking ethnic community has heterogeneous Indian ancestry [56]. Thus the genetic variations exhibit significant differences in the risk of developing various disorders and disease progression in the Pakistani population [15,57,58]..…”

Section: Discussionmentioning

confidence: 99%

MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study

et al. 2019

View full text Add to dashboard Cite

Background: To study the role of single nucleotide variants (SNVs) of genes related to preeclampsia in Pakistani pregnant women. Methods: After ethical approval and getting informed consent; 250 pregnant women were enrolled and equally divided into two groups (125 preeclamptic cases and 125 normotensive pregnant women). Demographic details and medical history were recorded, and 10 ml blood sample was obtained for DNA extraction. The tetra-primer amplification refractory mutation system (ARMS) assays were developed for assessing the variants of three preeclampsia related genes; F5, MTHFR and VEGFA. An association of six SNVs; F5:c.1601G > A (rs6025), F5:c.6665A > G (rs6027), MTHFR: c.665C > T (rs1801133), MTHFR: c.1286A > C (rs1801131), VEGFA: c.-2055A > C (rs699947) and VEGFA: c.*237C > T (rs3025039) with preeclampsia was determined by using different genetic models. Results: Genotyping of the SNVs revealed that patients with MTHFR:c.665C > T, have increased susceptibility to preeclampsia

show abstract

Implications of genetic variation of common Drug Metabolizing Enzymes and ABC Transporters among the Pakistani Population

Cited by 19 publications

References 58 publications

Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19

Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19

Functional phenotyping of the CYP2D6 probe drug codeine in the horse

MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study

Contact Info

Product

Resources

About