A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk. 