Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer.

Ethacrynic acid (EA) is an inhibitor of the glutathione S-transferases (GSTs), a family of detoxification enzymes the expression of which has been associated with resistance to several classes of anticancer drugs. We performed a two-way randomized crossover study to investigate the pharmacokinetics and bioavailability of EA and describe any toxicities of EA associated with i.v. administration. We administered EA (100 mg) either by the p.o. or i.v. route on days 1 and 2 for pharmacokinetic analysis. After i.v. administration, plasma EA disappearance was biphasic in seven patients and monophasic in two patients with a terminal half-life of 30 and 8 min, respectively. Mean total body clearance was high; 1405 ml/min in patients described by using a one-compartment model and 611 ml/min in those patients described by a two-compartment model. After p.o. administration, peak EA plasma concentrations were less than 10% of i.v. EA and the absolute bioavailability was less than 21% (range, 7-35%). The urinary output as a result of EA treatment was equal following either route of administration and together with the large first-pass effect suggests that a metabolite(s) may be the active diuretic agent(s). Burning at the injection site was the only toxicity unique to the i.v. route of EA administration. We concluded that the systemic availability of EA after p.o. administration is low and variable. This finding supports the potential utility of the i.v. route of administration for the treatment of drug resistance.