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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 (AUC last ), and extrapolated to infinity (AUC inf ), and the maximum plasma concentration (C max ) were determined. For both dextromethorphan and desipramine, AUC inf and C max 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 AUC inf , C max , 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.

Titel:	Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D617 and CYP2D629, When Compared with Normal Metabolizers.
Autor/in / Beteiligte Person:	Marasanapalle, VP ; Masimirembwa, C ; Sivasubramanian, R ; Sayyed, S ; Weinzierl-Hinum, A ; Mehta, D ; Kapungu, NN ; Kanji, C ; Thelingwani, R ; Zack, J
Link:	Full Text Finder (Volltext)
Zeitschrift:	Journal of clinical pharmacology, Jg. 64 (2024-05-01), Heft 5, S. 578-589
Veröffentlichung:	2013- : Oxford : Wiley ; <i>Original Publication</i>: Stamford, Conn., Hall Associates., 2024
Medientyp:	academicJournal
ISSN:	1552-4604 (electronic)
DOI:	10.1002/jcph.2366
Schlagwort:	Humans Adult Male Female Young Adult Healthy Volunteers Area Under Curve Black People genetics Middle Aged Half-Life Antidepressive Agents, Tricyclic pharmacokinetics Antidepressive Agents, Tricyclic blood Dextromethorphan pharmacokinetics Dextromethorphan blood Desipramine pharmacokinetics Desipramine blood Cytochrome P-450 CYP2D6 genetics Cytochrome P-450 CYP2D6 metabolism Genotype Alleles
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [J Clin Pharmacol] 2024 May; Vol. 64 (5), pp. 578-589. <i>Date of Electronic Publication: </i>2023 Oct 25. MeSH Terms: Dextromethorphan* / pharmacokinetics ; Dextromethorphan* / blood ; Desipramine* / pharmacokinetics ; Desipramine* / blood ; Cytochrome P-450 CYP2D6* / genetics ; Cytochrome P-450 CYP2D6* / metabolism ; Genotype* ; Alleles* ; Humans ; Adult ; Male ; Female ; Young Adult ; Healthy Volunteers ; Area Under Curve ; Black People / genetics ; Middle Aged ; Half-Life ; Antidepressive Agents, Tricyclic / pharmacokinetics ; Antidepressive Agents, Tricyclic / blood References: Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A review of the important role of CYP2D6 in pharmacogenomics. Genes (Basel). 2020;11:1295. ; Twesigomwe D, Drögemöller BI, Wright GEB, et al. 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Contributed Indexing: Keywords: CYP2D6 polymorphism; healthy African subjects; pharmacogenetics; pharmacokinetics Substance Nomenclature: 7355X3ROTS (Dextromethorphan) ; TG537D343B (Desipramine) ; EC 1.14.14.1 (Cytochrome P-450 CYP2D6) ; 0 (Antidepressive Agents, Tricyclic) Entry Date(s): Date Created: 20231007 Date Completed: 20240424 Latest Revision: 20240508 Update Code: 20240509

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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.

Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D617 and CYP2D629, When Compared with Normal Metabolizers.