Abstract
Purpose: Asian populations have around 40–60% frequency of reduced function allele CYP2D6∗10 compared to 1–2% in Caucasian populations. The wide range of CYP2D6 enzyme activities in subjects with the CYP2D6∗10 variant is a big concern for clinical practice. The quantitative analysis measuring the impact of CYP2D6 enzyme activity as a result of one CYP2D6∗10 allele or two CYP2D6∗10 alleles has not been reported in large Asian populations.Methods: A total of 421 healthy Chinese subjects were genotyped for CYP2D6 by polymerase chain reaction and direct DNA sequencing. A total of 235 subjects with CYP2D6∗1/∗1 (n = 22), CYP2D6∗1/∗10 (n = 93), CYP2D6∗10/∗10 (n = 85), and CYP2D6∗5/∗10 (n = 35) were phenotyped for CYP2D6 using dextromethorphan as the probe drug. Metabolic ratios (MR) were calculated as the ratio of parent drug to metabolite in 0–3 h urine, 3 h plasma, and 3 h saliva for each sample type.Results: The urinary, plasma, or salivary MRs increased successively in subjects with CYP2D6∗1/∗1, ∗1/∗10, ∗10/∗10, and ∗5/∗10 (all P < 0.001). In the normal metabolizer group, homozygous CYP2D6∗10/∗10 decreased the CYP2D6 enzyme activity further than heterozygous CYP2D6∗1/∗10. Urinary, plasma, and salivary MRs were highly correlated.Conclusion: The normal metabolizer group calls for a more detailed classification. The activity score system could more accurately predict enzyme activity than by grouping a number of genotypes into a single phenotype group. Single-point plasma samples and saliva samples could be used as alternative phenotyping methods for clinical convenience.
Highlights
The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme that is a member of the cytochrome P450 superfamily
The metabolic ratios (MR) from plasma collected 3, 4, or 6 h post-dose and MR from saliva collected 2, 3, 4, 5, 6 h post-dose were explored to discriminate between NM from PM and IM (Frank et al, 2007). These results showed that single-point plasma and saliva-derived MRs may serve as alternative tools for CYP2D6 phenotyping
According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline, subjects with CYP2D6∗1/∗1, ∗1/∗10, and ∗10/∗10 are classified as NMs, and subjects with CYP2D6∗5/∗10 are classified as IMs (Hicks et al, 2016)
Summary
The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme that is a member of the cytochrome P450 superfamily It plays an important role in the metabolism of approximately 25% of currently marketed drugs. The CYP2D6 gene product is one of the most famous and widely investigated polymorphic enzymes due to its broad inter-individual and inter-ethnic variations in enzyme activity. This led to the discovery of mutation, deletion, and duplication variants of the CYP2D6 gene (Teh and Bertilsson, 2012). Such diverse enzyme activities have been shown to result in dose-dependent adverse events or therapeutic failures after administration of CYP2D6 substrates (Gaedigk, 2013)
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