Atypical pharmacokinetics and excretion of new platinum analogues in rodents.
OBJECTIVE
Two new series of platinum complexes with cytotoxic activity in vivo are [Pt(NRCH2)2L2], (R=polyfluorophenyl, L=pyridine or substituted pyridine) and [Pt(NRCH2CH2NR'2)2L(X)], (R, L as before; R'=Me or Et, X=halogen). The aim of this study was to determine the pharmacokinetics and excretion in mice and in isolated perfused rat livers of a representative compound from each class, respectively: Pt103 (R=p-HC6F4, L=pyridine) and Pt109 (R, L as for Pt103, R'=Et, X=I).


METHODS
Mice were given intraperitoneal injections of active doses of Pt103, Pt109, or cisplatin in a variety of vehicles. Blood was sampled at several times to 48 h. Some mice were placed in metabolic cages where urine and feces were collected. In isolated, perfused rat livers, perfusate and bile were collected following a dose of Pt103, cisplatin or carboplatin. Platinum was measured in blood, urine, feces, or perfusate by atomic absorption spectroscopy. Three vehicles used were peanut oil, dimethyl sulphoxide, and saline/Tween 20.


RESULTS
In contrast to renal excretion of over 70% for cisplatin in saline, urinary excretion of platinum was less than 24% of a dose of Pt109 in peanut oil, less than 21% of P103 in DMSO, and only 4% for Pt103 in peanut oil. Over 60% of Pt103 was eliminated in mouse feces, and 57% was excreted in bile from rat liver. Plasma protein binding of Pt109 was greater than 90% at 6 h following administration in mice.


CONCLUSIONS
In contrast to cisplatin and carboplatin, representatives of two new classes of platinum anticancer agents undergo minimal renal elimination, but are excreted mainly in the bile and feces. If a platinum complex with a similar excretion profile was introduced into the clinic, there might be a therapeutic advantage in terms of drug toxicity and combination therapy with other cytotoxics.
Webster
Lorraine K
LK
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia. Lorraine.Webster@au.faulding.com
Ellis
Andrew G
AG
Apicella
Carmel
C
Deacon
Glen B
GB
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000652:urine; D010984:Platinum / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C448661:platinum 103; C448660:platinum 109; D010984:Platinum; D002945:Cisplatin