Clinical pharmacology of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193).

A pharmacokinetic study of tiazofurin was carried out in 13 patients treated in a phase I clinical trial of the drug and in 7 patients undergoing surgical resection of brain tumor (in conjunction with studies on penetration of drug into central nervous system tumors). Tiazofurin was found to be rapidly eliminated from the plasma and red blood cell fraction of both groups of patients with kinetics consistent with a two-compartment model of elimination. Operative conditions did not significantly change the pharmacokinetics of tiazofurin in CNS patients. Pharmacokinetics were linear over the dose range 500-2700 mg/m2. The data suggest that there is only a small degree of tissue binding of drug and that the drug is not concentrated by tissues. Uptake into RBC was rapid and elimination from RBC was essentially parallel to drug elimination from plasma. There was no evidence that RBC sequestration of drug contributes to toxicity. Much of the drug was excreted unchanged in the urine, but there was little correlation between creatinine clearance and plasma pharmacokinetics of tiazofurin, suggesting that renal tubular secretion may be a more important method of elimination than is glomerular filtration. Patients with high AUC values and low plasma clearance values were particularly prone to develop toxicity.