Biotransformation of the platinum drug JM216 following oral administration to cancer patients

Abstract

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.

Intracellular metabolism of the orally active platinum drug JM216: influence of glutathione levels

“…Our results show that some metabolites previously observed in patients' plasma ultrafiltrates can be observed intracellularly; those being A, JM383, D and JM 118 (Raynaud et al, , 1996. However, JM216 itself was never detected in patients' plasma ultrafiltrates and a late eluting metabolite F was not seen intracellularly and no JM559 could be measured.…”

“…Preclinical studies have shown that multiple administrations give the best anti-tumour responses (McKeage et al, 1994b) and this has been verified in patients, where multiple administrations could overcome the saturability in absorption observed in the single-dose study (McKeage et al, 1994c;Raynaud et al, 1995). It has been shown that JM216 is converted in patients' plasma into at least six different biotransformation complexes and that these biotransformation products are active in vitro and in vivo (Poon et al, 1995;Raynaud et al, 1996). Three of the metabolites present in patients have not yet been identified.…”

<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

“…Upon administration of satraplatin, a number of metabolites (JM118, JM383, JM518, JM559 and JM149) are formed [43]. Satraplatin and other platinum-based compounds exhibit anti-tumour activity via the formation of DNA crosslinks in vitro [44] which in turn results in specific cellular responses, namely, apoptosis and inhibition of transcription leading to arrest of cell replication [45][46][47].…”

A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473)

“…It also gives confidence that the exposure achieved in man (and therefore potential anticancer activity) is equivalent to that seen in the mouse models (Raynaud et al, 1997). In contrast to some other recently investigated novel platinum compounds such as satraplatin, AMD473 is not subject to extensive degradative metabolism (McKeage et al, 1995;Raynaud et al, 1996;Judson et al, 2000).…”