Evaluation of the pharmacological benefit and determination of the influencing factors of intraarterial cis-diamminedichloroplatinum administration in patients with uterine cervical cancer

Abstract

cis-Diamminedichloroplatinum (100 mg/m2) was administered to the same patients (n = 9) with advanced uterine cervical tumors, via i.v. and intraarterial (i.a.) (bilateral hypogastric arteries) routes. Measurement of plasma pharmacokinetic parameters enabled us to show up areas under the curve (AUC) of free cis-diamminedichloroplatinum versus time significantly (P less than 0.01) lower after i.a. injection (mean value, 3.9 mg.h/liter) than after i.v. injection (mean value, 5 mg.h/liter). However, the increase in intratumoral concentrations after i.a. administration was only at the limit of statistical significance (P = 0.05). Consequently, the benefit of local i.a. administration, evaluated according to the method of Collins, was small (1.2-2.3). An explanation of the phenomena observed can be given using the generalized compartmental model of Collins. We have demonstrated that the parameters of this model can be entirely calculated by taking into account both the i.v. and i.a. pharmacokinetic measurements. Calculations from experimental data of the model parameters, clearances of the body (ClB), and exchange rate between the site of administration and the rest of the body (Q) were in accordance with the physiological values. On the basis of the parameter values, it was confirmed that the low benefit of i.a. administration was due to the fast blood exchange between the injection site and the rest of the body and the probable cis-diamminedichloroplatinum binding on healthy tissues irrigated by the hypogastric artery.