The pharmacokinetics and metabolism of cyclosporin G (CsG; Sandoz compound OG 37-325) were studied in 12 healthy male volunteers receiving a single oral dose of 150 or 600 mg of [14C]CsG. Serial blood and plasma samples and complete urine and feces were collected for 120-hr postdose. CsG was rapidly absorbed, and the extent of absorption was dose-independent. Maximum blood concentrations of CsG at 2- to 3-hr postdose averaged 342 and 1170 ng/ml after doses of 150 and 600 mg, respectively, each accounting for approximately 50% of the blood radioactivity level. The plasma:blood concentration ratio for both CsG and total radioactivity averaged approximately 0.8. Overall disposition of absorbed CsG was independent of the dose. The drug was extensively metabolized with excretion predominantly via the fecal route. Total recovery in urine was only approximately 3% of the dose. In blood, the terminal half-life of CsG and total radioactivity averaged 9-11 hr following both the 150 and 600 mg doses. In plasma, the half-life of CsG was 2-4 hr and that of total radioactivity was 27-29 hr. The major metabolic pathways resulted from oxidative modifications at amino acids 1, 4, and 9, with concomitant cyclization of amino acid 1 in two metabolites. These pathways resulted in formation of seven major metabolites (designated GM19, GM1c9, GM4N9, GM1, GM9, GM1c, and GM4N) observed in human excreta and/or blood. Major metabolites of CsG in blood involved monohydroxylation (GM1 and GM9) or demethylation (GM4N). In blood, monohydroxylated CsG metabolites (GM1 and GM9) achieved roughly equal levels, with a trend toward higher GM9 concentrations at peak radioactivity.