title: Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats.
abstract: The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of correlation (> 0.8) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek/University Hospital Rotterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: W
authors.initials: W
authors.lastname: Van de Vrie
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: H J
authors.initials: HJ
authors.lastname: Kolker
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: G
authors.initials: G
authors.lastname: Stoter
authors.forename: N M
authors.initials: NM
authors.lastname: Durante
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003110:Colonic Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000970:Antineoplastic Agents; D004095:Dihydropyridines; D011725:Pyridines; C054074:niguldipine