Increased nonrenal clearance of cimetidine during antituberculous therapy.

To investigate the influence of antituberculous treatment on Cimetidin (Ci) disposition, 300 mg Ci were administered intravenously to 12 patients on triple drug therapy (Ethambutol 25 mg/kg/d, Isoniazid 8 mg/kg/d, Rifampicin (Rif) 8 mg/kg/d) and to 13 healthy subjects. Plasma levels and urinary recovery of Ci and its major metabolite Ci-Sulfoxide (CiS) were measured by HPLC. In patients on tuberculostatics nonrenal clearance (Clnr) increased by 52% (395 +/- 85 ml/min, controls 261 +/- 74 ml/min), while total clearance (ClB) (703 +/- 154 ml/min controls 632 +/- 118 ml/min) and volume of distribution (Vd beta) (1.35 +/- 0.33 l/kg, controls 1.6 +/- 0.37 l/kg) remained unchanged. The reduced renal clearance of Ci in the patients (308 +/- 125 ml/min, controls 371 +/- 115 ml/min) appeared to be mainly dependent on reduced renal function and not on antituberculous therapy. The CiS/Ci ratio in urine was unchanged in the patients (16 +/- 6.5, controls 20.5 +/- 10.6). The increased elimination of undegraded Ci via nonrenal pathways under tuberculostatic triple drug therapy may be a consequence of Rifampicin induced microsomal enzyme induction.