title: Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance.
abstract: The organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules, and inhibition of OCT2 protects against severe cisplatin-induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors, such as cimetidine, can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV-1 cells). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase-tagged IGROV-1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m(2)) in a randomized crossover fashion with or without cimetidine (800 mg × 2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs. 4.38 µg·h/ml; P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin-induced nephrotoxicity.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: J A
authors.initials: JA
authors.lastname: Sprowl
authors.forename: L
authors.initials: L
authors.lastname: van Doorn
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.forename: L
authors.initials: L
authors.lastname: van Gerven
authors.forename: P
authors.initials: P
authors.lastname: de Bruijn
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: A A
authors.initials: AA
authors.lastname: Gibson
authors.forename: R H
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002927:Cimetidine / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D002927:Cimetidine; D002945:Cisplatin