title: Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of cis-diamminedichloroplatinum.
abstract: Attenuation of the renal toxicity of cis-diamminedichloroplatinum (CDDP) is important in the use of this effective but cytotoxic anticancer agent. We have previously shown that the renal toxicity of CDDP can be efficiently reduced by the induction of metallothionein (MT) by preadministration of bismuth compounds in mice. Bismuth subnitrate (BSN) is used as an antigastric ulcer agent and as an antidiarrheic agent, and is suitable for inducing MT in the kidney in cancer patients. However, due to the low absorption rate of Bi from the gastrointestinal tract, the efficacy of BSN in inducing renal MT is low. In the present study, we examined the effects of citrate as a vehicle for oral administration of BSN on the tissue distribution of Bi and induction of MT in the kidneys and tumors in mice inoculated with Meth-A fibrosarcoma. Renal levels of MT and Bi were markedly increased in the mice given BSN dissolved in citrate solution compared with those given BSN suspended in saline. On the other hand, the use of citrate increased Bi accumulation in the tumor only slightly and did not increase tumor MT levels. Administration of BSN with citrate efficiently depressed the renal toxicity of CDDP, but did not affect its antitumor activity. Since both BSN and citrate are used clinically as pharmaceuticals, the combination regimen of BSN and citrate may be readily applicable as a countermeasure against the adverse side effects of CDDP without affecting its antitumor activity.
authors.affiliation: Department of Urology, Nippon Medical School, Bunkyo-ku, 114, Tokyo, Japan. kondoy@pharm.kitasato-u.ac.jp
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Kondo
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Himeno
authors.forename: Masahiko
authors.initials: M
authors.lastname: Satoh
authors.forename: Akira
authors.initials: A
authors.lastname: Naganuma
authors.forename: Taiji
authors.initials: T
authors.lastname: Nishimura
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Imura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001729:Bismuth / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000633:toxicity*; D019343:Citric Acid / Q000494:pharmacology*; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000517:prevention & control; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D020011:Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D020011:Protective Agents; D019343:Citric Acid; D008668:Metallothionein; C010804:bismuth subnitrate; D002945:Cisplatin; D001729:Bismuth