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The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans

Bedada, Worku MSc*; de Andrés, Fernando PhD; Engidawork, Ephrem BPharm, MSc, PhD*; Pohanka, Anton PhD; Beck, Olof PhD; Bertilsson, Leif PhD; Llerena, Adrián MD, PhD; Aklillu, Eleni BPharm, MSc, PhD

Journal of Clinical Psychopharmacology: December 2015 - Volume 35 - Issue 6 - p 694–699
doi: 10.1097/JCP.0000000000000413
Original Contributions
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The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12–1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20–72) and 31% (95% CI, 8–54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.

From the *Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; †CICAB Clinical Research Centre, Extremadura University Hospital and Medical School, Badajoz, Spain; and ‡Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, Stockholm, Sweden.

Received February 4, 2015; accepted after revision September 1, 2015.

Reprints: Eleni Aklillu, BPharm, MSc, PhD, Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, C-168 SE-141 86 Stockholm, Sweden (e-mail: Eleni.Aklillu@ki.se).

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