Measurements of 5,6 orthoquinone, surrogate for presumed active primaquine metabolite 5-hydroxyprimaquine, in the urine of Cambodian adults

The active metabolites of primaquine, in particular 5-hydroxyprimaquine, likely responsible for clearance of dormant hypnozoites, are produced through the hepatic CYP450 2D6 (CYP2D6) enzymatic pathway. With the inherent instability of 5-hydroxyprimaquine, a stable surrogate, 5,6 orthoquinone, can now be detected and measured in the urine as part of primaquine pharmacokinetic studies. This study performed CYP450 2D6 genotyping and primaquine pharmacokinetic testing, to include urine 5,6 orthoquinone, in 27 healthy adult Cambodians, as a preliminary step to prepare for future clinical studies assessing primaquine efficacy for Plasmodium vivax infections. The CYP2D6 *10 reduced activity allele was found in 57% of volunteers, and the CYP2D6 genotypes were dominated by *1/*10 (33%) and *10/*10 (30%). Predicted phenotypes were evenly split between Normal Metabolizer (NM) and Intermediate Metabolizer (IM) except one volunteer with a gene duplication and unclear phenotype, classifying as either IM or NM. Median plasma PQ area under the curve (AUC) was lower in the NM group (460 hr*ng/mL) compared to the IM group (561 hr*ng/mL), although not statistically significant. Similar to what has been found in the US study, no 5,6 orthoquinone was detected in the plasma. The urine creatinine-corrected 5,6 orthoquinone AUC in the NM group was almost three times higher than in the IM group, with peak measurements (T max ) at 4 hours. Although there is variation among individuals, future studies examining the relationship between the levels of urine 5,6 orthoquinone and primaquine radical cure efficacy could result in a metabolism biomarker predictive of radical cure.

Acute pharmacogenetic dystonic reactions in a family with the CYP2D6 *41 allele: a case report

Background Dystonia is a known neurological complication of certain medications; however, the mechanism behind such effects is often undetermined. Similarly, the clinical pharmacogenomic effects associated with various alleles of the cytochrome P450 family of proteins, and their role in acute dystonic reactions, are also presently unknown. Case presentation We describe a woman presenting with acute dystonic reactions to ondansetron, prochlorperazine, and metoclopramide followed by persistent focal dystonia. A similar family history was reported in her siblings and her father to prochlorperazine, drugs all metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Pharmacogenomic testing indicated the patient was heterozygous for the intermediate metabolizer *41 allele (CYP2D6 2988G>A, NM_000106.6:c.985+39G>A, rs28371725). Her father was homozygous for this CYP2D6 *41 allele, and consequently, her siblings were obligate carriers. Conclusions The metabolism of ondansetron, metoclopramide, or prochlorperazine in patients with the *41 CYP2D6 allele has not been studied. In this family, clinical evidence implicates the *41 CYP2D6 allele as causing extrapyramidal adverse pharmacologic reactions. Patients with a family history of medication-induced dystonia involving these medications should be considered for pharmacogenomic testing, and patients carrying the *41 CYP2D6 allele should consider reduction or avoidance of CYP2D6-mediated medications to minimize the potential risk of adverse extrapyramidal effects.

Severe Adverse Drug Reactions to Quetiapine in Two Patients Carrying CYP2D6*4 Variants: A Case Report

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.

Allele frequencies of single nucleotide polymorphisms of clinically important drug-metabolizing enzymes CYP2C9, CYP2C19, and CYP3A4 in a Thai population

Prior knowledge of allele frequencies of cytochrome P450 polymorphisms in a population is crucial for the revision and optimization of existing medication choices and doses. In the current study, the frequency of the CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*6, CYP2C19*17, and CYP3A4 (rs4646437) alleles in a Thai population across different regions of Thailand was examined. Tests for polymorphisms of CYP2C9 and CYP3A4 were performed using TaqMan SNP genotyping assay and CYP2C19 was performed using two different methods; TaqMan SNP genotyping assay and Luminex x Tag V3. The blood samples were collected from 1205 unrelated healthy individuals across different regions within Thailand. Polymorphisms of CYP2C9 and CYP2C19 were transformed into phenotypes, which included normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and rapid metabolizers (RM). The CYP2C9 allele frequencies among the Thai population were 0.08% and 5.27% for the CYP2C9*2 and CYP2C9*3 alleles, respectively. The CYP2C19 allele frequencies among the Thai population were 25.60%, 2.50%, 0.10%, and 1.80% for the CYP2C19*2, CYP2C19*3, CYP2C19*6, and CYP2C19*17 alleles, respectively. The allele frequency of the CYP3A4 (rs4646437) variant allele was 28.50% in the Thai population. The frequency of the CYP2C9*3 allele was significantly lower among the Northern Thai population (P < 0.001). The frequency of the CYP2C19*17 allele was significantly higher in the Southern Thai population (P < 0.001). Our results may provide an understanding of the ethnic differences in drug responses and support for the utilization of pharmacogenomics testing in clinical practice.

Identification of CYP2D6 allelic mutations in a sub-set of Karachi population

CYP2D6 gene polymorphism is considered a main obstacle in the process of drug metabolism under clinical diseases that affect pharmacokinetics of ~25% of antidepressants and other drugs. Inter-individual variation occurs in the amount and functional activity of CYP2D6 enzyme produce undesirable side effects. The primary aim of current research is to evaluate gene and genotypic frequencies of CYP2D6 *1 extensive metabolizer, *4 poor metabolizer and *10 intermediate metabolizer allelic variants among depressed patients and compared with normal subjects and other populations. Human genomic DNA was isolated. Genotyping was performed by Polymerase chain reaction followed by restriction endonucleases digestion for variants analysis. The results indicated gene frequency of CYP2D6*1 was 59% (CI 49.6,68.3%) in normal subjects whereas, CYP2D6*4 was 13% (CI 3.7, 22.3%) and CYP2D6*10 was 54% (44.7, 63.3%) predominantly found in depressed patients. The results demonstrate pronounced association of CYP2D6 *4 and *10 allelic variants with patient’s drug response activity.

Identification of CYP2D6 allelic mutations in a sub-set of Karachi population

CYP2D6 gene polymorphism is considered a main obstacle in the process of drug metabolism under clinical diseases that affect pharmacokinetics of ~25% of antidepressants and other drugs. Inter-individual variation occurs in the amount and functional activity of CYP2D6 enzyme produce undesirable side effects. The primary aim of current research is to evaluate gene and genotypic frequencies of CYP2D6 *1 extensive metabolizer, *4 poor metabolizer and *10 intermediate metabolizer allelic variants among depressed patients and compared with normal subjects and other populations. Human genomic DNA was isolated. Genotyping was performed by Polymerase chain reaction followed by restriction endonucleases digestion for variants analysis. The results indicated gene frequency of CYP2D6*1 was 59% (CI 49.6,68.3%) in normal subjects whereas, CYP2D6*4 was 13% (CI 3.7, 22.3%) and CYP2D6*10 was 54% (44.7, 63.3%) predominantly found in depressed patients. The results demonstrate pronounced association of CYP2D6 *4 and *10 allelic variants with patient’s drug response activity.

Influence of CYP2D6 gene polymorphisms on the pharmacokinetics of aripiprazole in healthy Chinese subjects

Background: Pharmacogenetics study was added into 2 bioequivalence trials of aripiprazole. The correlation between CYP2D6 polymorphisms and aripiprazole pharmacokinetics (PK) was analyzed. Materials & methods: A total of 140 subjects were included. A total of 26 CYP2D6 gene alleles were detected. The plasma concentration of aripiprazole was measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS). SPSS Statistics 21 was used to analyze the correlation between CYP2D6 polymorphisms and aripiprazole PK parameters. Results: All of the four PK parameters were significantly influenced by CYP2D6 rs1058164 and rs28371699. t1/2 and area under the concentration-time curve (AUC0–∞) exhibited significant difference between CYP2D6 extensive metabolizers and intermediate metabolizers. Conclusion: Aripiprazole PK was greatly influenced by CYP2D6. Attention should be paid to the possible dose adjustment for CYP2D6 intermediate metabolizer population when the drug is used in Chinese patients.

Effect of CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of CYP2D6*10

Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.