title: The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans.
abstract: 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.
authors.affiliation: 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.
authors.forename: Worku
authors.initials: W
authors.lastname: Bedada
authors.forename: Fernando
authors.initials: F
authors.lastname: de Andrés
authors.forename: Ephrem
authors.initials: E
authors.lastname: Engidawork
authors.forename: Anton
authors.initials: A
authors.lastname: Pohanka
authors.forename: Olof
authors.initials: O
authors.lastname: Beck
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.forename: Adrián
authors.initials: A
authors.lastname: Llerena
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000328:Adult; D029754:Catha; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects* / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000235:genetics; D003915:Dextromethorphan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D003917:Dextrorphan / Q000097:blood; D005002:Ethiopia; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D008297:Male; D018515:Plant Leaves; D055815:Young Adult
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018691:Excitatory Amino Acid Antagonists; D003917:Dextrorphan; C028657:3-methoxymorphinan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human