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
I
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.