Phenotypic and Genotypic Evaluation of Catha Edulis F. (Khat) Effect on Cytochrome P450 Mediated Drug Metabolism
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Date
2016-06
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Addis Ababa University
Abstract
Khat (Catha edulis Forsk) is an evergreen perennial plant that belongs to Celestraceae family. The plant is cultivated primarily in East Africa and the Arabian Peninsula, harvested and then chewed to obtain stimulant effect. Khat is freely available in Ethiopia and has become popular among all segments of the population. Thus, it is highly likely that khat could be chewed while users are on medications. Ingestion of khat might affect bioavailability of concurrently taken medications, which in turn alter safety and/or efficacy. Bioavailability of drugs depends to a significant degree on the extent of elimination by cytochrome P450 (CYP) enzymes. CYP enzymes are influenced by genetic as well as non-genetic factors. Five major CYPs, namely CYP3A, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 are responsible for the metabolism of over 99% of currently marketed drugs.
In an attempt to study the impact of khat on concurrently taken medications, the metabolic activities (phenotype) of these five CYPs were assessed in absence and presence of khat using appropriate probe drugs. The impacts of genetic variants (genotype) of the enzymes were also studied. To this effect, a comparative one-way crossover study was carried out on healthy Ethiopian adult habitual khat chewing volunteers to evaluate the effect of khat on CYP in two phases. Phase I was a pilot study involving the two major enzymes CYP2D6 and CYP3A enzymes, while in phase II five major CYPs were studied. After one week of abstinence from khat, blood samples were collected from 40 (phase I) and 60 (phase II) subjects to assess the baseline metabolic activities of the enzymes using 30 mg dextromethorphan (DM) (CYP3A and CYP2D6), 50 mg losartan (CYP2C9), 20 mg omeprazole (CYP2C19) and 100 mg caffeine (CYP1A2) as probe drugs. The procedure was repeated after one week of daily regular intake of 400 g fresh khat. DSM-V criteria for stimulant withdrawal and urinary cathinone level were employed to monitor the subjects' compliance to the study protocol. The metabolic activities were assessed by comparing the median metabolic ratio (MR) of DM/3-methoxymorphinan (3-MM), DM/ (dextrorphan) DX, losartan/ losartan carboxylic acid, omeprazole/5-hydroxyomeprazole and caffeine/ paraxanthine for CYP3A, CYP2D6, CYP2C9, CYP2C19 and
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CYP1A2, respectively. Wilcoxon Signed Ranks Test was used to compare the median MR in the absence and presence of khat.
The median DM/DX was significantly increased in the presence of khat in phase I (P=0.02) and in phase II (P=0.001) as well as when the data from both phases were merged (P=0.001). Moreover, the effect was particularly evident with CYP2D6 *1/*1 (P=0.001) compared to CYP2D6*1/*4 and CYP2D6*4/*4. Although the median DM/3-MM was only marginally increased in phase I (P=0.09), it was significantly increased in phase II (P=0.045) and when the data were merged (P=0.001). Even for phase I, the effect was significant (P=0.02) when an outlier was excluded. However, since CYP3A genotyping data were available for phase II alone and valid phenotype data in phase II were small, it was difficult to associate these data with phenotyping results. On the other hand, khat had no significant effect on the metabolic activities of CYP1A2 (P=0.71), CYP2C9 (P=0.64) and CYP2C19 (P=0.15). In addition, the logMR of probe drugs/metabolites in the presence of khat were correlated with logMR of cathinone/cathine using spearman correlation test for non-parametric tests. Consequently, moderately significant correlations were observed for CYP2D6, CYP2C9 and CYP3A, which indicate that khat is a substrate for these enzymes. Insignificant correlations were seen for CYP1A2 and CYP2C19. To the best of our knowledge, the present study is the first to investigate the impact of habitual khat consumptions on in vivo activity of human drug metabolizing enzymes. The results of the present study indicate that khat produces significant and reproducible inhibitory effects on the two major enzymes, CYP2D6 and CYP3A, which are responsible for metabolism of over 75% currently marketed drugs. The inhibitory effects of khat were consistently demonstrated by genotyping data for CYP2D6, but not for CYP3A enzyme. Moreover, the two major enzymes appeared to be involved in the metabolism of khat as seen from the correlation tests. Although the clinical significance of the current study is yet to be determined, it would be better to refrain from khat chewing while on medication to avoid potentially detrimental interactions. Keywords: khat, Cytochrome P450 enzymes, Probe drugs, Phenotype, Genotype, Cathinone, Cathine, drug interaction
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Keywords
khat, Cytochrome P450 enzymes, Probe drugs, Phenotype, Genotype