Effects of histamine-2 receptor blockade on lidocaine kinetics

The hypothesis that the H₂-receptor blockers cimetidine and ranitidine have different effects on the disposition of lidocaine, a microsomally metabolized drug dependent on hepatic blood flow for elimination, was tested. Six normal men received lidocaine infusions (2 mg/kg over 10 minutes) and lidocaine levels were determined by HPLC. Lidocame kinetics were studied in the untreated state (O) and in a doubleblind, double-dummy design after 2 days of placebo (P), cimetidine (C, 300 mg every 6 hours by mouth), or ranitidine (R, 160 mg every 12 hours by mouth). Model-independent kinetics were estimated by the statistical moment theory. The steady-state volume of distribution was lower after cimetidine (X ± SD: O, 156 ± 39 L; P, 156 ± 48 L; C, 123 ± 20 L; and R, 174 ± 38 L). A trend toward decreased lidocaine clearance after cimetidine was also noted (O, 1011 ± 140 ml/min; P, 1087 ± 227 ml/min; C, 886 ± 214 ml/min; and R, 1143 ± 225 ml/min). Elimination rate constants were of the same order in all four treatments. Only higher levels of α₁-acid glycoprotein appeared to limit the lidocaine steady-state volume of distribution. Cimetidine and ranitidine have distinctly different effects on lidocaine kinetics in normal subjects. The absence of ranitidine effects on the disposition of lidocaine, a high-extraction, high-clearance drug, suggests that H₂-receptor blockade may not decrease hepatic blood flow, and that cimetidine impairs drug elimination only by inhibition of hepatic microsomal enzymes. Such interactions are not likely to occur with ranitidine.