The impact of catha edulis (vahl) forssk. ex endl. (celestraceae) (khat) on pharmacokinetics of clinically used drugs

References

• Nigg HN, Seigler D, editors. Phytochemical Resources for Medicine and Agriculture [Internet]. US:Springer; 1992. cited 2021 Jun 14]. Available from: https://www.springer.com/gp/book/9780306442452.
   Google Scholar
• Gu C, Tembrock LR, Zheng S, et al. The complete chloroplast genome of catha edulis: a comparative analysis of genome features with related species. Int J Mol Sci. 2018;19(2):525.
   Web of Science ®Google Scholar
• World Health Organization. Thirty-fourth report/WHO Expert Committee on Drug Dependence: Geneva, 28-31 March 2006. Geneva: World Health Organization; 2006.
   Google Scholar
• Griffiths P, Lopez D, Sedefov R, et al. Khat use and monitoring drug use in Europe: the current situation and issues for the future. J Ethnopharmacol. 2010;132(3):578–583.
   PubMed Web of Science ®Google Scholar
• Csete J European policy on khat: drug policy lessons not learned. Global Drug Policy Observatory. [Internet]. Global Drug Policy Observatory, 2014. [cited 2021 Apr 14]. Available from: https://www.swansea.ac.uk/media/European-Policy-on-khat–Drug-Policy-lessons-not-learned.pdf.
   Google Scholar
• Abbott KL, Flannery PC, Gill KS, et al. Adverse pharmacokinetic interactions between illicit substances and clinical drugs. Drug Metab Rev. 2020;52(1):44–65.
   PubMed Web of Science ®Google Scholar
• At W, Cheme MC, Kibret KT, et al. Perceived psychological, economic, and social impact of khat chewing among adolescents and adults in Nekemte Town, East Welega Zone, West Ethiopia. BioMed Res Int. 2017;2017:1–9.
   Web of Science ®Google Scholar
• Getasetegn M. Chemical composition of catha edulis (khat): a review. Phytochem Rev. 2016;15(5):907–920.
   Web of Science ®Google Scholar
• Rizk M, Mobarak M, El-Shihi T, et al. Constituents of catha edulis (alkaloids, triterpenoids and related substances and saponins). Qatar Univ Sci J. 1989;9:55–64.
   Google Scholar
• AL-Jalali A, Shaltout A. Natural radioactivity of catha edulis (khat) and tobacco plants collected from Yemen. Int J Innov. 2014;2:350–354.
   Google Scholar
• Matloob MH. Determination of cadmium, lead, copper and zinc in Yemeni khat by anodic stripping voltammetry. East Mediterr Health J. 2003;9:28–36.
   PubMedGoogle Scholar
• Atlabachew M, Chandravan BS, Redi M, et al. Profile of major, minor and toxic metals in soil and khat (catha edulis F.) cultivars in Ethiopia. Trends Appl Sci Res. 2011;6:640–655.
   Google Scholar
• Wabe N, Mohammed M. What science says about khat (catha edulis F.)? overview of chemistry, toxicology and pharmacology. J Exp Integr Med. 2012;2: 29.
   Google Scholar
• Tembrock LR, Broeckling CD, Heuberger AL, et al. Employing two-stage derivatization and GC-MS to assay for cathine and related stimulant alkaloids across the celastraceae: GC-MS assay for stimulant alkaloids across the celastraceae. Phytochem Anal. 2017;28:257–266.
   PubMed Web of Science ®Google Scholar
• Valente MJ, Guedes de Pinho P, de Lourdes Bastos M, et al. Khat and synthetic cathinones: a review. Arch Toxicol. 2014;88:15–45.
   PubMed Web of Science ®Google Scholar
• Baxter RL, Crombie L, Simmonds DJ, et al. Alkaloids of catha edulis(khat). Part 1. Isolation and characterization of eleven new alkaloids with sesquiterpene cores (cathedulins); identification of the quinone–methide root pigments. J Chem Soc Perkin Trans. 1979;1:2965–2971.
   Google Scholar
• Crombie L. The cathedulin alkaloids. Bull Narc. 1980;32:37–50.
   PubMedGoogle Scholar
• Kim T-S, White JD. The absolute configuration of edulinic acid, a constituent of the “Khat” alkaloid cathedulin K-19. Tetrahedron Lett. 1993;34(35):5535–5536.
   Web of Science ®Google Scholar
• Kubo I, Kim M, De Boer G, et al. Efficient isolation of insect growth inhibitory macrolide alkaloids using recycle high-performance gel permeation chromatography. J Chromatogr A. 1987;402:354–357.
   Web of Science ®Google Scholar
• Toennes SW, Harder S, Schramm M, et al. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves: pharmacokinetics of khat alkaloids. Br J Clin Pharmacol. 2003;56(1): 125–130.
   PubMed Web of Science ®Google Scholar
• Toennes SW, Kauert GF. Excretion and detection of cathinone, cathine, and phenylpropanolamine in urine after khat chewing. Clin Chem. 2002;48:1715–1719.
   PubMed Web of Science ®Google Scholar
• Krizevski R, Dudai N, Bar E, et al. Developmental patterns of phenylpropylamino alkaloids accumulation in khat (catha edulis, F.). J Ethnopharmacol. 2007;114:432–438.
   PubMed Web of Science ®Google Scholar
• Bedada W, de Andrés F, Engidawork E, et al. The psychostimulant khat (catha edulis) inhibits CYP2D6 enzyme activity in humans. J Clin Psychopharmacol. 2015;35(6): 694–699.
   PubMed Web of Science ®Google Scholar
• Bedada W, de Andrés F, Engidawork E, et al. Effects of khat (catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations. Sci Rep. 2018;8(1): 12726.
   PubMedGoogle Scholar
• Engidawork E. Pharmacological and toxicological effects of catha edulis F. (khat): khat pharmacology and toxicology. Phytother Res. 2017;31:1019–1028.
   PubMed Web of Science ®Google Scholar
• Dhaifalah I, Šantavý J. Khat habit and its health effect: a natural amphetamine. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2004;148:11–15.
   PubMedGoogle Scholar
• Colzato LS, Sellaro R, Ruiz M, et al. Acute khat use reduces response conflict in habitual users. Front Hum Neurosci. 2013;7:285.
   PubMed Web of Science ®Google Scholar
• Pehek E, Schechter M, Yamamoto B, et al. Effects of cathinone and amphetamine on the neurochemistry of dopamine in vivo. Neuropharmacology. 1990;29(12):1171–1176.
   PubMed Web of Science ®Google Scholar
• Dawson BA, Black DB, Lavoie A, et al. Nuclear magnetic resonance identification of the phenylalkylamine alkaloids of khat using a chiral solvating agent. J Forensic Sci. 1994;39(4):13681J.
   Web of Science ®Google Scholar
• Kalix P. The releasing effect of the isomers of the alkaloid cathinone at central and peripheral catecholamine storage sites. Neuropharmacology. 1986;25(5):499–501.
   PubMed Web of Science ®Google Scholar
• Kalix P. Khat: a plant with amphetamine effects. J Subst Abuse Treat. 1988;5(3):163–169.
   PubMed Web of Science ®Google Scholar
• Feyissa AM, Kelly JP. A review of the neuropharmacological properties of khat. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(5):1147–1166.
   PubMed Web of Science ®Google Scholar
• Hoffman R, al’Absi M. Working memory and speed of information processing in chronic khat users: preliminary findings. Eur Addict Res. 2013;19:1–6.
   PubMed Web of Science ®Google Scholar
• Geresu B, Engidawork E. Catha edulis F. (khat) reverses haloperidol but not morphine induced motor deficits following acute and subacute administration in mice. Eth Pharm J. 2010;28:117–130.
   Google Scholar
• Afify EA, Alkreathy HM, Ali AM, et al. Characterization of the antinociceptive mechanisms of khat extract (catha edulis) in mice. Front Neurol. 2017;8:69.
   PubMed Web of Science ®Google Scholar
• Geresu B, Onaivi E, Engidawork E, et al. Behavioral evidence for the interaction between cannabinoids and catha edulis F. (khat) in mice. Brain Res. 2016;1648:333–338.
   PubMed Web of Science ®Google Scholar
• Geresu B, Canseco-Alba A, Sanabria B, et al. Involvement of CB2 receptors in the neurobehavioral effects of catha edulis (vahl) endl. (khat) in mice. Molecules. 2019;24(17):3164.
   Web of Science ®Google Scholar
• Admassie E, Engidawork E. Subchronic administration of Catha edulis F. (khat) extract is marked by elevation of cardiac biomarkers and subendocardial necrosis besides blood pressure alteration in rats. J Ethnopharmacol. 2011;136(1):246–253.
   PubMed Web of Science ®Google Scholar
• Asrade S, Shibeshi W, Engidawork E, et al. Evaluation of the reversibility and possible mechanisms of antifertility of catha edulis F. (khat) extract following subacute administration in rodents. Afr J Phar Pharmacol. 2013;7:2693–2700.
   Google Scholar
• Riyaz S. Khat (catha edulis) as a possible cause of autoimmune hepatitis. World J Hepatol. 2014;6(3):150.
   PubMedGoogle Scholar
• Fujikura K, Ingelman-Sundberg M, Lauschke VM, et al. Genetic variation in the human cytochrome P450 supergene family. Pharmcogenet Genomics. 2015;25:584–594.
   PubMed Web of Science ®Google Scholar
• Fatunde OA, Brown S-A. The role of CYP450 drug metabolism in precision cardio-oncology. Int J Mol Sci. 2020;21(2):604.
   Web of Science ®Google Scholar
• Peñas-LLedó EM, LLerena A. CYP2D6 variation, behavior and psychopathology: implications for pharmacogenomics-guided clinical trials: CYP2D6 and personality. Br J Clin Pharmacol. 2014;77:673–683.
   PubMed Web of Science ®Google Scholar
• Masimirembwa CM, Gustafsson LL, Dahl M, et al. Lack of effect of chloroquine on the debrisoquine (CYP2D6) and S‐mephenytoin (CYP2C19) hydroxylation phenotypes. Br J Clin Pharmacol. 1996;41:344–346.
   PubMed Web of Science ®Google Scholar
• Gaedigk A, Sangkuhl K, Whirl-Carrillo M, et al. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69–76.
   PubMed Web of Science ®Google Scholar
• Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multi-duplicated functional CYP2D6 alleles. J Pharmacol Exp Ther. 1996;278:441–446.
   PubMed Web of Science ®Google Scholar
• McLellan RA, Oscarson M, Seidegard J, et al. Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics. 1997;7:187–191.
   PubMedGoogle Scholar
• Qumsieh RY, Ali BR, Abdulrazzaq YM, et al. Identification of new alleles and the determination of alleles and genotypes frequencies at the CYP2D6 gene in Emiratis. PLoS One. 2011;6(12):e28943.
   PubMed Web of Science ®Google Scholar
• Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5(1):6–13.
   PubMed Web of Science ®Google Scholar
• Petrović J, Pešić V, Lauschke VM, et al. Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe. Eur J Hum Genet. 2020;28(1):88–94.
   PubMed Web of Science ®Google Scholar
• Aklillu E, Herrlin K, Gustafsson LL, et al. Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics. 2002;12(5):375–383.
   PubMedGoogle Scholar
• Van Booven D, Marsh S, McLeod H, et al. Cytochrome P450 2C9-CYP2C9. Pharmacogenet Genomics. 2010;20(4):277–281.
   PubMed Web of Science ®Google Scholar
• Daly A, Rettie A, Fowler D, et al. Pharmacogenomics of CYP2C9: functional and clinical considerations. J Pers Med. 2017;8(1):1.
   PubMed Web of Science ®Google Scholar
• Hatta FHM, Lundblad M, Ramsjo M, et al. Differences in CYP2C9 genotype and enzyme activity between Swedes and Koreans of relevance for personalized medicine: role of ethnicity, genotype, smoking, age, and sex. OMICS. 2015;19:346–353.
   PubMed Web of Science ®Google Scholar
• Ramsjö M, Aklillu E, Bohman L, et al. CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking. Eur J Clin Pharmacol. 2010;66(9):871–877.
   PubMed Web of Science ®Google Scholar
• Persson I, Aklillu E, Rodrigues F, et al. S-mephenytoin hydroxylation phenotype and CYP2C19 genotype among Ethiopians. Pharmacogenetics. 1996;6(6):521–526.
   PubMedGoogle Scholar
• Sim S, Risinger C, Dahl M, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006;79(1):103–113.
   PubMed Web of Science ®Google Scholar
• Niwa T, Emoto C, Murayama N, et al. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr Drug Metab. 2008;9:20–33.
   PubMed Web of Science ®Google Scholar
• Diczfalusy U, Miura J, Roh H-K, et al. 4β-Hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians. Pharmacogenet Genomics. 2008;18(3):201–208.
   PubMed Web of Science ®Google Scholar
• Gebeyehu E, Engidawork E, Bijnsdorp A, et al. Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians. Pharmacogenomics J. 2011;11(2):130–137.
   PubMed Web of Science ®Google Scholar
• Thorn CF, Aklillu E, Klein TE, et al. PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenet Genomics. 2012;22(1):73–77.
   PubMed Web of Science ®Google Scholar
• Djordjevic N, Ghotbi R, Bertilsson L, et al. Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol. 2008;64(4):381–385.
   PubMed Web of Science ®Google Scholar
• Ghotbi R, Christensen M, Roh H-K, et al. Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol. 2007;63(6):537–546.
   PubMed Web of Science ®Google Scholar
• Djordjevic N, Ghotbi R, Jankovic S, et al. Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 −163C>A polymorphism. Eur J Clin Pharmacol. 2010;66(7):697–703.
   PubMed Web of Science ®Google Scholar
• Sakuyama K, Sasaki T, Ujiie S, et al. Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57). Drug Metab Dispos. 2008;36(12):2460–2467.
   PubMed Web of Science ®Google Scholar
• Lim SYM, Binti Azidin AR, Ung YT, et al. Effect of 95% Ethanol khat extract and cathinone on in vitro human recombinant cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 activity. Eur J Drug Metab Pharmacokinet. 2019;44:423–431.
   PubMed Web of Science ®Google Scholar
• Sh K, Sharma A, Ti K, et al. Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids. Toxicol Lett. 2020;319:148–154.
   PubMed Web of Science ®Google Scholar
• Wang L, Hai Y, Huang N, et al. Human cytochrome P450 enzyme inhibition profile of three flavonoids isolated from psoralea corylifolia: in silico predictions and experimental validation. New J Chem. 2018;42:10922–10934.
   Web of Science ®Google Scholar
• Qu Q, Qu J, Han L, et al. Inhibitory effects phytochemicals on metabolic capabilities of CYP2D6*1 and CYP2D6*10 using cell-based models in-vitro. Acta Pharmacol Sin. 2013;35:685–696.
   Web of Science ®Google Scholar
• Krajka-Kuzniak V, Duowska B. The effects of tannic acid on cytochrome P450 and phase II enzymes in mouse liver and kidney. Toxicol Lett. 2003;143(2):209–216.
   PubMed Web of Science ®Google Scholar
• Attef O. Effect of khat chewing on the bioavailability of ampicillin and amoxycillin. J Antimicrob Chemother. 1997;39(4):523–525.
   PubMed Web of Science ®Google Scholar
• Ghani YMA, Etman MA, Nada AH, et al. Effect of khat chewing on the absorption of orally administered amoxicillin. (1999). Acta Pharm (Croatia). 1999;49(1):43–50.
   Google Scholar
• Abdulkarim K. Cephradine bioequivalence and its interaction with khat and food (al-sayadeyah) in Yemen. [Internet] [MSc.]. University of Khartoum, 2004. [cited 2021 Apr 30]. Available from: http://hdl.handle.net/123456789/8058.
   Google Scholar
• Al-Mekhlafi AG. The effect of chewing khat on drug absorption: a case study of pharmacokinetic profiles of ciprofloxacin 500 mg tablets. Int J Pharm Pharm Res. 2020;18(4):415–428.
   Google Scholar
• Farah FH, Attef OA, A-aa A, et al. The influence of khat on the in-vitro and in-vivo availability of Tetracycline-HCl. Res J Pharma Dosage Forms Tech. 2015;7:1.
   Google Scholar
• Issa FH, Al-Habori M, Chance ML, et al. Effect of khat (catha edulis) use on the bioavailability, plasma levels and antimalarial activity of Chloroquine. Sultan Qaboos Univ Med J. 2016;16(2):e182–188.
   PubMedGoogle Scholar
• Projean D, Baune B, Farinotti R, et al. In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Dispos. 2003;31:748–754.
   PubMed Web of Science ®Google Scholar
• Bennett JW, Pybus BS, Yadava A, et al. Primaquine failure and cytochrome P-450 2D6 in plasmodium vivax malaria. N Engl J Med. 2013;369(14):1381–1382.
   PubMed Web of Science ®Google Scholar
• Daher A, Aljayyoussi G, Pereira D, et al. Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine. Malar J. 2019;18:325.
   PubMed Web of Science ®Google Scholar
• Alkadi HO, Al-Kamarany M, Al-Kadi H, et al. Khat–aspirin interaction. Yemen J Pharm Biol Sci. 2008;2:32–39.
   Google Scholar
• Alhazmi HA, Kadi AA, Attwa MW, et al. Exploring the effect of khat (catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique. Open Chem. 2020;18(1):681–690.
   Web of Science ®Google Scholar
• Bouman HJ, Schömig E, Van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011;17(1):110–116.
   PubMed Web of Science ®Google Scholar
• Tselepis AD, Tsoumani ME, Kalantzi KI, et al. Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy: PON-1 and platelet reactivity in ACS patients. J Thromb Haemost. 2011;9(12):2371–2378.
   PubMed Web of Science ®Google Scholar
• Bonello L, Camoin-Jau L, Armero S, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol. 2009;103(1):5–10.
   PubMed Web of Science ®Google Scholar
• Sibbing D, Koch W, Massberg S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J. 2011;32(13):1605–1613.
   PubMed Web of Science ®Google Scholar
• Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5(12):2429–2436.
   PubMed Web of Science ®Google Scholar
• Collet J-P, Hulot J-S, Anzaha G, et al. High doses of clopidogrel to overcome genetic resistance. JACC: Cardiovasc Interv. 2011;4:392–402.
   PubMed Web of Science ®Google Scholar
• Hulot J-S. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244–2247.
   PubMed Web of Science ®Google Scholar
• Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics. 2007;17(12):1057–1064.
   PubMed Web of Science ®Google Scholar
• Mega JL, Simon T, Collet J-P, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16): 1821.
   PubMed Web of Science ®Google Scholar
• Hwang S-J, Jeong Y-H, Kim I-S, et al. The cytochrome 2C19*2 and *3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention. Thromb Res. 2011;127(1):23–28.
   PubMed Web of Science ®Google Scholar
• Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363–375.
   PubMed Web of Science ®Google Scholar
• Sofi F, Giusti B, Marcucci R, et al. Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J. 2011;11(3):199–206.
   PubMed Web of Science ®Google Scholar
• Shuldiner AR. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849.
   PubMed Web of Science ®Google Scholar
• El Rouby N, Lima JJ, Johnson JA, et al. Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug Metab Toxicol. 2018;14(4):447–460.
   PubMed Web of Science ®Google Scholar
• Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther. 1999;65(5):552–561.
   PubMed Web of Science ®Google Scholar
• Furuta T. Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19. Clin Pharmacol Ther. 2001;70(5):484–492.
   PubMed Web of Science ®Google Scholar
• Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 2006;58:521–590.
   PubMed Web of Science ®Google Scholar
• Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH: CYP2C19 genotype: omeperazole vs. rabeprazole. Aliment Pharmacol Ther. 2001;15(12):1929–1937.
   PubMed Web of Science ®Google Scholar
• Qiao H-L, Hu Y-R, Tian X, et al. Pharmacokinetics of three proton pump inhibitors in Chinese subjects in relation to the CYP2C19 genotype. Eur J Clin Pharmacol. 2006;62(2):107–112.
   PubMed Web of Science ®Google Scholar
• Lou H-Y, Chang -C-C, Sheu M-T, et al. Optimal dose regimens of esomeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism. Eur J Clin Pharmacol. 2009;65(1):55–64.
   PubMed Web of Science ®Google Scholar
• Albaser NA, Mohamad AWH, AL-Kamarany MA, et al. Khat-drug interactions: a systematic review. J Pharm Pharmacogn Res. 2021;9:333–343.
   Web of Science ®Google Scholar
• Erah P. The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of helicobacter pylori infection. J Antimicrob Chemother. 1997;39(1):5–12.
   PubMed Web of Science ®Google Scholar
• Elkady EF, Fouad MA, Alshoba N, et al. Validated LC–MS/MS method for the determination of some prescribed CNS drugs: application to an in vivo pharmacokinetic study of drug-herb metabolic interaction potential of khat. Microchem. 2020;158:105261.
   Web of Science ®Google Scholar
• Weli AM, El-Shaibany A. Interference of khat with treatment of paranoid schizophrenia. Int J Chem Pharm Sci. 2011;2:1–11.
   Google Scholar
• Kotb El Sayed M, Amin H-K. Catha edulis chewing effects on treatment of paranoid schizophrenic patients. Neuropsychiatr Dis Treat. 2015;11:1067–1076.
   PubMed Web of Science ®Google Scholar
• Aniszewski T. Alkaloids - secrets of life: alkaloid chemistry, biological significance, applications and ecological role. 1st ed. Amsterdam, Boston: Elsevier; 2007.
   Google Scholar
• Bamashmus M, Othrob NY, Mousa A, et al. Effect of khat (qat) consumption on pain during and after local anesthesia for patients undergoing cataract surgery. Med Sci Monit. 2010;16:SR29–33.
   PubMed Web of Science ®Google Scholar
• Bamgbade OA. The perioperative implications of khat use. Eur J Anesthesiol. 2008;25: 170–172.
   PubMed Web of Science ®Google Scholar
• Mion G. Chronic amphetamine users do not need more drugs during general anesthesia. Anesth Analg. 2017;124(6):2092–2093.
   PubMed Web of Science ®Google Scholar
• Kuypers DRJ, Claes K, Evenepoel P, et al. The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients. Drug Metab Dispos. 2004;32:1421–1425.
   PubMed Web of Science ®Google Scholar
• Bellībaş SE, Tuĝlular I, Kayali A, et al. The effect of delayed gastric emptying and absorption on pharmacokinetic parameters of lithium. Eur J Drug Metab Pharmacokinet. 1995;20(2):129–133.
   PubMed Web of Science ®Google Scholar
• Verbeurgt P, Mamiya T, Oesterheld J, et al. How common are drug and gene interactions? prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genotyping. Pharmacogenomics. 2014;15(5):655–665.
   PubMed Web of Science ®Google Scholar
• Kapelyukh Y, Wolf R CYP2D6 substrates and drug metabolism. In: Baumann P. (ed) CYP2D6: Genetics, Pharmacology and Clinical Relevance [Internet]. Unitec House, 2 Albert Place, London N3 1QB, UK: Future Medicine Ltd. 2014. [ cited 2021 Jun 14]. Available at: http://www.futuremedicine.com/doi/book/10.2217/9781780844626.
   Google Scholar
• LLerena A, Naranjo MEG, Rodrigues-Soares F, et al. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metab Toxicol. 2014;10:1569–1583.
   PubMed Web of Science ®Google Scholar
• Cheng J, Zhen Y, Miksys S, et al. Potential role of CYP2D6 in the central nervous system. Xenobiotica. 2013;43(11):973–984.
   PubMed Web of Science ®Google Scholar
• Haduch A, Bromek E, Sadakierska-Chudy A, et al. The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Pharmacol Res. 2013;67(1):53–59.
   PubMed Web of Science ®Google Scholar
• Aklillu E, Kalow W, Endrenyi L, et al. CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics. 2007;17(11):989–993.
   PubMed Web of Science ®Google Scholar
• Yitna E, Mossie A, Yami A, et al. Effects of khat (catha edulis) on bronchial asthma. (2018). Open J Asthma. 2018;2(1):5–10.
   Google Scholar
• Alshagga MA, Alshawsh MA, Seyedan A, et al. Khat (catha edulis) and obesity: a scoping review of animal and human studies. Ann Nutr Metab. 2016;69(3–4):200–211.
   PubMed Web of Science ®Google Scholar