Metabolism, protein binding and in vivo activity of the oral platinum drug JM216 and its biotransformation products

This study evaluates the metabolism of the oral platinum drug JM216 [bis(acetato) amminedichloro(cyclo-hexylamine)platinum (IV)] following oral administration to Balb C - mice. JM216 was detectable 1h post administration in mice but not in patients. Also, a late eluting metabolite observed in patients was not detected in mice. JM118 [amminedichloro(cyclohexylamine) platinum (II)], the platinum II species which is the major metabolite in patients was rapidly converted following i.v. administration to a compound having the same retention time as JM383 [bis(acetato)ammine(cyclohexylamine)dihydroxo platinum(IV)/ indicating that the levels of JM383 following JM216 administration have probably been overestimated. The metabolite D observed in patients for which a structure has not been assigned, was also detected in mice. However, it did not originate from arty of the identified biotransformation products. The protein binding evaluated in plasma, and buffer with physiological levels of albumin and globulin showed that only Platinum (II) species have significant binding and that JM118 showed the same affinity to albumin and globulin (t 1/2 of 4.2 and 4.8h) while cisplatin bound more readily to albumin (t 1/2 3.4h) than globulin IV (t 1/2 8.2h). JM216 itself failed to bind to either of the proteins tested indicating extensive reduction in patients, animals or plasma incubation medium. JM118 and JM518 [bis(acetato)amminechloro (cyclohexylamine) hydroxoplatinum (IV)] were significantly more active than the platinum IV complexes JM216 and JM383 when given ip. to ADJ/PC6 plasmacytoma bearing mice (ED 90 of 1.0 and 0.4 versus 5.7 and 4.2 mg/kg, Tl (therapeutic index) of 14 and 37 versus 5.3 and 4.2). When given orally, JM216 was the most potent drug (ED 90 of 5.8 versus 11, J2 and 42 mg/kg and TI of 57 versus 12 12 and 16) for JM118 and JM383. There data indicates that JM216 biotransformation products are potent but that the levels of JM383 determined in out analytical conditions could have been overestimated.