Wechselwirkungen zwischen bioaktiven Sekundärmetaboliten und Irinotecan

Zusammenfassung

Irinotecan wird seit mehr als zwei Jahrzehnten in unterschiedlichen Arzneiformen, auch in Kombination mit anderen Arzneistoffen, zur Behandlung einiger Tumorerkrankungen eingesetzt. Irinotecan, ein Prodrug, wird über die Butyrylcholinesterase und über die Carboxylesterasen CES1 und CES2 in die aktive Form SN-38 (7-Ethyl-10-hydroxycamptothecin) verstoffwechselt. SN-38 ist ein starker Topoisomerase-I-Inhibitor. Aufgrund des komplexen Metabolisierungsweges von Irinotecan und wegen der engen therapeutischen Breite des Arzneistoffes ist die klinische Relevanz einer Interaktion zwischen bioaktiven Sekundärmetaboliten und Irinotecan von vielen unterschiedlichen Einflussfaktoren abhängig und kann daher nur im Rahmen einer individualmedizinischen Betreuung Bedeutung haben. Sowohl die Butyrylcholinesterase und die Carboxylesterasen CES1, CES2 als auch CYP3A4, CYP3A5, UGT1A-Isoforme und Transportproteine sind an der Verstoffwechselung und Eliminierung von Irinotecan beteiligt und limitieren die Verfügbarkeit des aktiven Metaboliten SN-38. Inhibition oder Induktion dieser Enzyme durch bioaktive Sekundärmetabolite könnten die therapeutische Wirksamkeit des Irinotecan-Metaboliten SN-38 beeinflussen und für die Ausbildung von Nebenwirkungen ursächlich sein. Der folgende Artikel versucht, einige mögliche Interaktionen abzuschätzen und aufzuzeigen.

Abstract

Irinotecan has been used for more than two decades in various pharmaceutical forms, also in combination with other drugs, for the treatment of some tumor diseases. Irinotecan, a prodrug, is metabolised via butyrylcholinesterase and via the carboxylesterases CES1 and CES2 into the active form SN-38 (7-ethyl-10-hydroxycamptothecin). SN-38 is a strong topoisomerase I inhibitor. Due to the complex metabolic pathway of Irinotecan and because of the narrow therapeutic range of the drug substance, the clinical relevance of an interaction between bioactive secondary metabolites and Irinotecan depends on many different influencing factors and can therefore only be of importance in the context of individual medical care. Butyrylcholinesterase and the carboxylesterases CES1, CES2 as well as CYP3A4, CYP3A5, UGT1A-isoforms and transport proteins are involved in the metabolism and elimination of Irinotecan and limit the availability of the active metabolite SN-38. Inhibition or induction of these enzymes by bioactive secondary metabolites could influence the therapeutic efficacy of the Irinotecan metabolite SN-38 and be causative for the development of side effects. The following article attempts to assess and demonstrate some possible interactions.

Schlüsselwörter

Irinotecan - SN-38 - bioaktive Sekundärmetabolite - Metabolismus

Key words

Irinotecan - SN-38 - interaction - bioactive secondary metabolites - metabolism

• Literatur

• 1 Bokemeyer C. Irinotecan – klinischer Fortschritt in der Second-line-Therapie des fortgeschrittenen Kolorektalkarzinoms. Onkologie 2000; 23 (Suppl. 6) 28-31
• 2 Bailly C. Irinotecan: 25 years of cancer treatment. Pharmacol Res 2019; 148: 104398
• 3 Yang Y, Zhou M, Hu M. et al. UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan-induced toxicity: A meta-analysis. Asia Pac J Clin Oncol 2018; 14: 479-489
• 4 Kronabel D. Interaktion von Lebensmitteln und Onkologika: Die klinische Relevanz ist entscheidend. Dtsch Z Onkol 2016; 48: 100-103
• 5 Wang D, Zou L, Jin Q. et al. Human carboxylesterases: a comprehensive review. Acta Pharm Sin B 2018; 8: 699-712
• 6 De Man FM, Goey AKL, van Schaik RHN. et al. Individualization of irinotecan treatment: A review of pharmacokinetics, pharmacodynamics, and pharmacogenetics. Clin Pharmacokinet 2018; 57: 1229-1254
• 7 Santos A, Zanetta S, Cresteil T. et al. Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 2000; 6: 2012-2020
• 8 Buck E, Sprick M, Gaida MM. et al. Tumor response to irinotecan is associated with CYP3A5 expression in colorectal cancer. Oncol Lett 2019; 17: 3890-3898
• 9 Xu J, Qiu JC, Ji X. et al. Potential pharmacokinetic herb-drug interactions: Have we overlooked the importance of human carboxylesterases 1 and 2?. Curr Drug Metab 2019; 20: 130-137
• 10 Merali Z, Ross S, Paré G. The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact 2014; 29: 143-151
• 11 Parker RB, Hu ZY, Meibohm B. et al Effects of alcohol on human carboxylesterase drug metabolism. Clin Pharmacokinet 2015; 54: 627-638
• 12 van der Bol JM, Mathijssen RH, Loos WJ. et al. Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 2007; 25: 2719-2726
• 13 Weng ZM, Ge GB, Dou TY. et al. Characterization and structure-activity relationship studies of flavonoids as inhibitors against human carboxylesterase 2. Bioorg Chem 2018; 77: 320-329
• 14 Krasowski MD, McGehee DS, Moss J. Natural inhibitors of cholinesterases: Implications for adverse drug reactions. Can J Anaesth 1997; 44: 525-534
• 15 Yang AK, He SM, Liu L. et al. Herbal interactions with anticancer drugs: mechanistic and clinical considerations. Curr Med Chem 2010; 17: 1635-1678
• 16 Mirkov S, Komoroski BJ, Ramírez J. et al. Effects of green tea compounds on irinotecan metabolism. Drug Metab Dispos 2007; 35: 228-233
• 17 Misaka S, Kawabe K, Onoue S. et al. Effects of green tea catechins on cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal microsomes. Drug Metab Pharmacokinet 2013; 28: 244-249
• 18 Lown KS, Bailey DG, Fontana RJ. et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545-2553
• 19 Yang J, Yan B. Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor. Toxicol Sci 2007; 95: 13-22
• 20 Li M, Wang Z, Guo J. et al. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 2014; 7: 1653-1661
• 21 Abudahab S, Hakooz N, Jarrar Y. et al. Interethnic variations of UGT1A1 and UGT1A7 polymorphisms in the Jordanian population. Curr Drug Metab 2019; 20: 399-410
• 22 Tziotou M, Kalotychou V, Ntokou A. et al. Polymorphisms of uridine glucuronosyltransferase gene and irinotecan toxicity: low dose does not protect from toxicity. Ecancermedicalscience 2014; 8: 428
• 23 Kalthoff S, Ehmer U, Freiberg N. et al. Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology 2010; 9: 1699-1710
• 24 Strassburg C. Analysen zur Toxizität und therapeutischen Modifikation des Chemotherapeutikums Camptothecin. Forschungsvorhaben der DFG; Projektkennung: Deutsche Forschungsgemeinschaft (DFG), Projektnummer 282635917
• 25 Nozawa T, Minami H, Sugiura S. et al. Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 2005; 33: 434-439
• 26 Fujita D, Saito Y, Nakanishi T. et al Organic anion transporting polypeptide (OATP)2B1 contributes to gastrointestinal toxicity of anticancer drug SN-38, active metabolite of irinotecan hydrochloride. Drug Metab Dispos 2016; 44: 1-7
• 27 Wang EJ, Casciano CN, Clement RP. et al Inhibition of P-glycoprotein transport function by grapefruit juice psoralen. Pharm Res 2001; 18: 432-438
• 28 Mandery K, Balk B, Bujok K. et al. Inhibition of hepatic uptake transporters by flavonoids. Eur J Pharm Sci 2012; 46: 79-85
• 29 Shirasaka Y, Shichiri M, Murata Y. et al. Long-lasting inhibitory effect of apple and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption. Drug Metab Dispos 2013; 41: 615-621
• 30 Nielsen DL, Palshof JA, Brünner N. et al. Implications of ABCG2 expression on irinotecan treatment of colorectal cancer patients: A review. Int J Mol Sci 2017; 18: 1926
• 31 Yoshikawa M, Ikegami Y, Sano K. et al. Transport of SN-38 by the wild type of human ABC transporter ABCG2 and its inhibition by quercetin, a natural flavonoid. J Exp Ther Oncol 2004; 4: 25-35
• 32 Lei CS, Hou YC, Pai MH. et al. Effects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studies. J Nutr Biochem 2018; 51: 105-113
• 33 Tong T, Niu YH, Yue Y. et al. Beneficial effects of anthocyanins from red cabbage (Brassica oleracea L. var. capitata L.) administration to prevent irinotecan-induced mucositis. J Functional Foods 2017; 32: 9-17