| Biotransformation of the platinum drug JM216 following oral administration to cancer patients. | |
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MedLine Citation:
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PMID: 8616906 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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This study evaluates the metabolic profile of JM216 [bis(acetato)ammine-dichloro(cyclohexylamine) platinum(IV)], the first orally administrable platinum complex, in plasma ultrafiltrates of 12 patients (n = 2-4 time points per patient) following different doses of drug (120, 200, 340, 420, 560 mg/m2). The biotransformation profile was evaluated by high-performance liquid chromatography (HPLC) followed by atomic absorption spectrophotometry (AA). The AA profiles were compared with those previously identified by HPLC on line with mass spectrometry (HPLC-MS) in plasma incubated with JM216. A total of six platinum peaks (Rt = 5.5, 7.2, 10.6, 12.4, 15.6, and 21.6 min, respectively) were observed in patients' plasma ultrafiltrate samples, of which only four appeared during the first 6 h post-treatment. Four of these coeluted with those observed and identified previously in plasma incubation medium. No parent JM216 was detected. The major metabolite seen in patients was the Pt II complex JM118 [cis-amminedichloro-(cyclohexylamine)platinum(II)] and was observed in all the patients. Interestingly, the second metabolite was shown to coelute with the Pt IV species JM383 [bis-acetatoammine(cyclohexylamine)dihydroxoplatinum (IV)]. Both JM118 and JM383 were identified by HPLC-MS in a clinical sample. Peak C, which was a minor product (less than 5% of the free platinum), coeluted with JM559 [bis-acetatoammine-chloro(cyclohexylalamine)hydroxoplatin um(IV)]. The cytotoxicity profile of all three metabolites in a panel of cisplatin-sensitive and -resistant human ovarian carcinoma cell lines was very close to that of the parent drug. In addition, the concentrations of JM118 reached in patients' plasma ultrafiltrate were comparable with the cytotoxic levels of the compound determined in the ovarian carcinoma panel of cell lines. Two metabolites were seen in patients but not in the in vitro incubation medium, suggesting the involvement of a possible enzymatic reaction. Thus, the biotransformation profile following oral administration of JM216 shows a variety of Pt(IV) and Pt(Il) metabolites in plasma that differ significantly from other systemically applied platinum drugs. |
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Authors:
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F I Raynaud; P Mistry; A Donaghue; G K Poon; L R Kelland; C F Barnard; B A Murrer; K R Harrap |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 38 ISSN: 0344-5704 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 1996 |
Date Detail:
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Created Date: 1996-06-11 Completed Date: 1996-06-11 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: GERMANY |
Other Details:
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Languages: eng Pagination: 155-62 Citation Subset: IM |
Affiliation:
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Institute of Cancer Research, CRC Centre for Cancer Therapeutics, Sutton, Survey, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Antineoplastic Agents / administration & dosage, chemistry, metabolism*, therapeutic use Cell Death / drug effects Chromatography, High Pressure Liquid Female Humans Molecular Structure Organoplatinum Compounds / administration & dosage, chemistry, metabolism*, therapeutic use Ovarian Neoplasms Platinum / blood Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Organoplatinum Compounds; 129580-63-8/satraplatin; 7440-06-4/Platinum |
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