Drug interactions associated with excretion are typically attributed to renal impairment, either a result of the parent drug, or with co-administration with nephrotoxic agents.1 Most kinase inhibitors undergo hepatic elimination and faecal excretion, with variable renal clearance.1-11
An interesting consideration is the effect of the renal expression of drug transporter proteins - including P-glycoprotein, organic anion transporting peptides, organic cation transporter and breast cancer resistance protein - in terms of the elimination of kinase inhibitors and effects on the co-administration of chemotherapy agents.1 For instance, because of the possible inhibition of the organic cation transporter by erlotinib, accumulation of cisplatin in renal tubular cells was thought to be inhibited, with the potential of preventing cisplatin-associated nephrotoxicity.12 Similarly, a drug interaction between imatinib and methotrexate has been postulated to affect the transport and elimination of methotrexate, an effect which may occur through drug transporter proteins.13 However, the positive effects of renal drug transporter changes on the pharmacokinetics of kinase inhibitors and on the toxicity profile of co-administered chemotherapy agents requires further elucidation.1
- van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
- Abbas R, Hug BA, Leister C et al. A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol 2012; 69: 221-227.
- de Wit D, van Erp NP, Khosravan R et al. Effect of gastrointestinal resection on sunitinib exposure in patients with GIST. BMC Cancer 2014; 14: 575.
- Yoo C, Ryu MH, Kang BW et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. J Clin Oncol 2010; 28: 1554-1559.
- Kim KP, Ryu MH, Yoo C et al. Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. Cancer Chemother Pharmacol 2011; 68: 285-291.
- Castellino S, O'Mara M, Koch K et al. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab Dispos 2012; 40: 139-150.
- Christopher LJ, Cui D, Wu C et al. Metabolism and disposition of dasatinib after oral administration to humans. Drug Metab Dispos 2008; 36: 1357-1364.
- Deng Y, Sychterz C, Suttle AB et al. Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica 2013; 43: 443-453.
- Gschwind HP, Pfaar U, Waldmeier F et al. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos 2005; 33: 1503-1512.
- Martin P, Oliver S, Kennedy SJ et al. Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. Clin Ther 2012; 34: 221-237.
- Speed B, Bu HZ, Pool WF et al. Pharmacokinetics, distribution, and metabolism of [14C]sunitinib in rats, monkeys, and humans. Drug Metab Dispos 2012; 40: 539-555.
- Sprowl JA, Mathijssen RH, Sparreboom A. Can erlotinib ameliorate cisplatin-induced toxicities? J Clin Oncol 2013; 31: 3442-3443.
- Breedveld P, Pluim D, Cipriani G et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 2005; 65: 2577-2582.