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The comparative effects of continuous versus intermittent cimetidine infusion on theophylline pharmacokinetics were evaluated in 12 nonsmoking healthy male volunteers. Each subject received aminophylline 0.9 mg/kg/hr over 6 hours alone (control) and in random order at 1 week intervals, in combination with intermittent cimetidine (300 mg IV over 15 minutes every 6 hours) and continuous cimetidine (50 mg/hr IV) infusions. Both cimetidine regimens were administered for a total of 50 hours. Serial plasma samples were obtained and assayed for theophylline by HPLC. No significant differences existed in mean theophylline clearance and mean volume of distribution among control, intermittent or continuous cimetidine regimens; the power was greater than 80% to detect a 30% change in clearance. Only a minor difference in theophylline half-life between control and continuous cimetidine infusion (7.59 +/- 2.52 vs. 9.05 +/- 3.17 hr; P less than .05) was observed. These findings do not support a clinically significant interaction between IV aminophylline and cimetidine administered IV either as a low dose continuous infusion or as an intermittent infusion.

The effect of cimetidine on the single dose pharmacokinetics of carbamazepine was examined in nine male Sprague-Dawley rats after the administration of a 25 mg/kg iv dose of carbamazepine. Five rats received a concomitant 50 mg/kg iv dose of cimetidine. Concomitant cimetidine administration produced a decrease in carbamazepine clearance (liters/hr/kg) (0.68 +/- 0.037 vs. 0.41 +/- 0.091; p less than 0.002) which was accompanied by an increase in carbamazepine half-life (hr) (1.1 +/- 0.16 vs. 2.0 +/- 0.37; p less than 0.003). No cimetidine-induced alterations in the volume of distribution at steady-state (liters/kg) occurred (1.1 +/- 0.14 vs. 1.2 +/- 0.04; NS). A reduction in the partial area under the plasma concentration-time curve for carbamazepine-10, 11-epoxide (mg X hr/liter) (28 +/- 2.5 vs. 18 +/- 3.7; p less than 0.002) with cimetidine treatment suggests that a portion of the reduction in carbamazepine clearance may be the result of cimetidine-induced inhibition of epoxide formation. The effect of cimetidine on epoxide formation was further substantiated using an in vitro rat liver homogenate preparation where inhibition of epoxide formation by cimetidine occurred in a dose-dependent fashion.

1 The pharmacokinetic parameters of morphine were determined in a crossover fashion following 4 days pretreatment with cimetidine, 300 mg every 6 h, or placebo. 2 Cimetidine had no apparent effect on the mean morphine plasma clearance, volume of distribution, AUC or half-life (P greater than 0.05; power greater than 0.80). 3 Cimetidine had no apparent effect on the magnitude or duration of morphine induced miosis. 4 The absence of a demonstrable effect on the pharmacokinetics of a drug with a high extraction ratio such as morphine suggests that cimetidine did not significantly reduce hepatic blood flow in ambulant normal volunteers.

The effect of cimetidine on the single-dose pharmacokinetics of pentoxifylline and one of its major metabolites, 3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (1), was examined in two groups of male Sprague-Dawley rats (6 rats/group) after the administration of pentoxifylline (1 mg/kg) alone and following a 50 mg/kg iv dose of cimetidine. The addition of cimetidine resulted in a 37% decrease in pentoxifylline clearance (23.8 +/- 7.5 versus 15.0 +/- 3.2 mL/min; p less than 0.03). No changes in the volume of distribution of pentoxifylline or in the total area under the plasma concentration-time curve for 1 were observed with the addition of cimetidine. The mechanism of this metabolic interaction is probably cimetidine-induced inhibition of hepatic microsomal enzymes, which blocks the major excretory pathways for pentoxifylline. Further studies are warranted in humans to determine the existence and clinical significance of this interaction.

The effects of cimetidine and a new, potent H2-antagonist, famotidine, on the single dose pharmacokinetics of theophylline were examined in rats. Male Sprague-Dawley rats (6 rats/group) received an i.v. dose of theophylline (6 mg/kg) alone and in conjunction with an i.v. dose of famotidine (10 mg/kg) or cimetidine (10 mg/kg). Venous blood samples were collected serially for seven hours after theophylline infusion and analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0- infinity; 38.1 +/- 8.7 vs. 38.8 +/- 6.3 micrograms.hr.ml-1), while cimetidine demonstrated a significant reduction in theophylline systemic clearance (0.11 +/- 0.02 vs. 0.16 +/- 0.02 L/hr/kg; p less than 0.001), a 40% prolongation of half-life (2.8 +/- 0.9 vs. 2.0 +/- 0.5 hr), with no change in the volume of distribution (0.39 +/- 0.1 vs. 0.41 +/- 0.13 L/kg). These results suggest that in contrast to cimetidine, famotidine, a non-imidazole H2-receptor antagonist, does not interfere with theophylline disposition in the rat.

Prednisone is a glucocorticoid that must be converted in vivo to prednisolone for pharmacologic activity. We examined the effects of the H2-receptor antagonists cimetidine and ranitidine on the time course of plasma prednisolone concentrations after an oral dose of prednisone. Nine healthy men received each of three oral treatments in a double-blind, balanced, crossover manner: cimetidine (300 mg every 6 hours), ranitidine (150 mg twice a day), or placebo for 4 days, with prednisone (40 mg) taken also on day 4. Serial blood and urine samples were collected for 30 hours after prednisone dosing. Prednisone and prednisolone plasma and urine concentrations were analyzed by HPLC. No differences were found between treatments in the maximum prednisolone plasma concentration, t1/2, apparent volume of distribution, and AUC. Cimetidine reduced the mean (+/- SD) ratio of prednisone dose to the plasma prednisolone AUC (16.6 +/- 2.9 L/hr) below that ratio after ranitidine (19.2 +/- 4.2 L/hr) and placebo (19.3 +/- 2.8 L/hr), and resulted in the lowest fractional excretion of prednisolone in the urine (5.2% +/- 2.2%, 9.8% +/- 4.5%, and 12.4% +/- 4.9%, respectively). The minor alterations in prednisolone kinetics during concomitant cimetidine dosing are not likely to induce clinically significant alterations in steroid effect.

Controversy exists as to whether H2-receptor antagonists decrease hepatic blood flow. This study examined the effect of single doses of cimetidine 300 and 600 mg po on apparent hepatic blood flow as estimated by indocyanine green (ICG) clearance. A double-blind, repeated-measure study was performed in nine supine healthy men. Following an overnight fast, placebo or cimetidine was administered one hour prior to ICG 0.5 mg/kg iv. Plasma samples were obtained serially for a period of 20 minutes following dye administration and stored at -70 degrees until high performance liquid chromatographic analysis. Cimetidine had no apparent effect on mean +/- SD ICG clearance following placebo, cimetidine 300 mg, and cimetidine 600 mg (366 +/- 66 vs. 336 +/- 55 vs. 350 +/- 58 ml/min/m2, respectively; NS). Corresponding values for estimated hepatic blood flow were 632 +/- 109, 580 +/- 103, and 617 +/- 112 ml/min, respectively; NS. No statistically significant changes in ICG half-life or volume of distribution at steady state occurred as a function of treatment. Contrary to previous reports, single-dose cimetidine administration appeared to have no appreciable effect on hepatic blood flow. These results implicate cimetidine binding to the cytochrome P-450 system as the sole mechanism responsible for inhibition of the systemic clearance of co-administered drugs metabolized by the liver.

Conflicting data exists regarding the effect of the H2-receptor blocking agent cimetidine on hepatic blood flow (HBF). The variance in the results of these studies may be due in part to differences in the duration of cimetidine administration, the posture of the volunteers during their course of study, and the method used to estimate HBF. To assess the effects of chronic cimetidine (300 mg q.i.d. X 4 days) on estimated HBF while controlling posture (supine and standing), a double-blind, placebo-controlled, repeated measures study was performed in 9 healthy males. Indocyanine green (ICG) plasma clearance after an i.v. dose of 0.5 mg kg-1 was used to calculate HBF. ICG plasma concentrations were measured by HPLC. Compared to placebo treatment, cimetidine had no effect on mean (SD) estimated HBF (ml min-1 m-2) in either the supine (497 (64) vs 494 (80] or the standing (443 (117) vs 404 (89] posture. These data had a power greater than 0.8 to detect a treatment effect of 20 per cent. Standing produced a significant decrease in estimated HBF (496 (70) vs 424 (102); p less than 0.01). In contrast to previous reports, chronic cimetidine treatment had no apparent effect on hepatic blood flow.