Clinical pharmacology of intraarterial cis-diamminedichloroplatinum(II)

After intraarterial (30 patients) or i.v. (seven patients) administration of cis-diamminedichloroplatinum, X-ray fluorescence spectrometry was used to measure platinum concentrations in plasma and urine. Arteries infused included hepatic (seven patients), carotid (six patients), iliac (ten patients), brachial (three patients), and femoral (four patients). All patients received i.v. mannitol. Pharmacokinetic parameters after intraarterial administration were similar to those after i.v. administration, although differences existed for different intraarterial routes of administration. Mean for all patients combined were: Co, 2.67 +/- 0.97 (S.D.) microgram/ml; t1/2 beta, 71.1 +/- 26.6 hr; clearance, 0.72 +/- 0.25 liters/hr/sq m; total volume of distribution, 45.2 +/- 17.0 liters/sq m; C x t, 167 +/- 72 mg/hr/liter; and 24-hr urinary excretion, 20 +/- 10% of the administered dose. Intrahepatic infusion of the drug was associated with a significantly lower Co (1.88 +/- 0.50 g/ml) and C x t (140 +/- 25 mg hr/liter) and significantly higher clearance (0.91 +/- 0.24 liters/hr/sq m) and volume of distribution (67.6 +/- 4.6 liters/sq m) than administration by other routes, suggesting first pass extraction of drug by liver. In addition, an apparent minor late rise in serum platinum concentration may suggest enterohepatic recirculation of drug. High fluid intake was associated with a low Co and a high volume of distribution, consistent with expansion of the central compartment by fluids. Low serum albumin (less than 3.5 g/dl) was associated with significant shortening of the t1/2 beta (50.5 +/- 21.6 hr), suggesting that the amount of unbound filterable drug may possibly be higher in patients with low serum albumin concentrations. Plasma from veins draining an infused area has a higher Co and C x t during infusion than concurrent plasma from peripheral veins. Thus, intraarterial administration of cis-diamminedichloroplatinum results in increased drug exposure of tumor in the infused area without substantially decreasing exposure of systemic tumor.