Cimetidine induces reversible dose-related central nervous system (CNS) toxicity. Trough serum concentrations and the development of CNS toxicity correlate. We compared cimetidine kinetics in 12 healthy subjects and 31 patients. Six of the latter had normal renal and liver function, five had renal disease only, 12 had liver disease only, and eight had both renal and liver disease. Postmortem tissue distribution was assessed in 11 patients, and expressed as tissue:serum ratio. Average cimetidine total clearance (ClB) in milliliters per minute for each group was as follows: patients with renal and liver disease (182 +/- 105), renal disease only (193 +/- 24), liver disease only (463 +/- 145), normal patients (510 +/- 93), and healthy subjects (583 +/- 140). Renal function was the major determinant for ClB, and the relationship was described by ClB = 4.2(CCr) + 140, r = 0.87, where CCr is creatinine clearance. Cimetidine clearance was affected little by age. Tissue:serum ratios from highest to lowest were as follows: kidney greater than stomach greater than liver greater than bone greater than brain greater than fat. Central and steady-state distribution volumes were not influenced by age or disease. There was enchanced CNS penetration in liver disease patients; their cerebrospinal fluid (CSF):serum ratio was twice the normal. Our kinetic studies identify patient characteristics likely to result in elevated blood levels, and suggest that the greatest risk of CNS toxicity is in those with liver disease.