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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers
Journal of Clinical Pharmacology, Year 2023
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Description
This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration–time curve from time of dosing to time of last quantifiable concentration (AUClast), and extrapolated to infinity (AUCinf), and the maximum plasma concentration (Cmax) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUCinf, Cmax, and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings. © 2023, The American College of Clinical Pharmacology.
Authors & Co-Authors
Masimirembwa, Collen Mutowembwa
Zimbabwe, Harare
African Institute of Biomedical Science and Technology Aibst
Sayyed, Sarfaraz
Unknown Affiliation
Kapungu, Nyasha Nicole
Zimbabwe, Harare
African Institute of Biomedical Science and Technology Aibst
Kanji, Comfort Ropafadzo
Zimbabwe, Harare
African Institute of Biomedical Science and Technology Aibst
Thelingwani, Roslyn Stella
Zimbabwe, Harare
African Institute of Biomedical Science and Technology Aibst
Statistics
Citations: 1
Authors: 5
Affiliations: 2
Identifiers
Doi:
10.1002/jcph.2366
ISSN:
00912700
Research Areas
Genetics And Genomics
Health System And Policy
Study Design
Cohort Study