Single Dose Of Cimetidine Research Articles

The role of organic cation transporter 2 inhibitor cimetidine, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats

PurposeWe investigated the influence of diabetes mellitus (DM), glycemic control with insulin, cimetidine (Oct2 inhibitor) and metformin (Oct2 substrate) on the kinetic disposition of GAB in rats. Main methodsMale Wistar rats were divided in five groups and all animals received an oral dose of 50 mg/kg GAB: (vehicle + GAB), cimetidine + GAB (single dose of cimetidine [100 mg/kg] intraperitoneally 1 h before GAB), metformin + GAB (single dose of metformin 100 mg/kg by gavage concomitantly with GAB), DM + GAB (single dose of 40 mg/kg streptozotocin (STZ) intravenously) and DM + GAB + insulin (single dose 40 mg/kg STZ intravenously and 2 IU insulin twice daily for 15 days). Pharmacokinetic analysis was based on plasma and urine data concentrations. Key findingsNo differences in pharmacokinetic parameters were observed between vehicle + GAB × cimetidine + GAB and vehicle + GAB × metformin + GAB groups. Diabetes increased the fraction of GAB excreted unchanged in urine (vehicle + GAB: 0.48 [0.38–0.58]; DM + GAB: 0.83 [0.62–1.04]; DM + GAB + insulin: 0.88 [0.77–0.93]) (mean [95% confidence interval]) without any changes in GAB exposure. Insulin treated diabetic animals showed higher renal clearance compared to control (vehicle + GAB: 0.25 [0.18–0.30] L/h·kg; DM + GAB + insulin: 0.55 [0.45–1.43] L/h·kg), which was attributed to the diabetes-induced glomerular hyperfiltration. SignificanceGlomerular filtration is the main mechanism of renal excretion of GAB without significant contribution of Oct2 active transport.

Behavioral and metabolic aspects of cimetidine-ethanol interaction

The effect of cimetidine, an H 2 histamine receptor blocker, on spontaneous locomotor activity and ethanol-produced narcosis was studied in the male mouse. The separate and combined effects of cimetidine, and histalog (betazol), an H 2 histamine receptor agonist, on voluntary intake of diluted ethanol solution by the rat were also determined. The in vitro effect of cimetidine on rat liver alcohol and aldehyde dehydrogenase was assayed. Cimetidine treatment was associated with an initial moderate increase in locomotor activity which was increased significantly as a function of time. The central depressant action of ethanol, as measured by duration of ethanol-mediated narcosis, was decreased by pretreatment with a single dose of cimetidine. The drug did not alter voluntary drinking of ethanol by the rat but antagonized histalog-produced aversion to ethanol selection when administered prior to histalog. Cimetidine, 3 × 10 −3 M concentration, inhibited rat liver aldehyde dehydrogenase but not alcohol dehydrogenase in vitro. The results indicate cimetidine-ethanol interaction and suggest the implication of histamine in some of the ethanol-elicited responses studied.

DOES PRETREATMENT WITH CIMETIDINE AND RANITIDINE AFFECT THE DISPOSITION OF BUPIVACAINE ?

Thirty patients who chose extradural analgesia for elective Caesarean section were pretreated, by random selection, with cimetidine 400 mg, ranitidine 150 mg or no H2-blocker. Following the administration of 0.5% bupivacaine, no significant difference was found between peak plasma bupivacaine concentrations or area under the plasma bupivacaine concentration-time curve (AUC) in these three groups. This study shows that a single dose of cimetidine or ranitidine does not affect significantly the disposition of bupivacaine in the obstetric patient.

Effect of enzyme induction and inhibition on the fate of metronidazole and tinidazole in the rat.

The excretion routes of intact metronidazole and tinidazole were studied in rats kept in metabolism cages and cannulated for continuous bile collection. The nitroimidazoles were given intraarterially either alone or after a 5-day pretreatment with phenobarbitone (70 mg/kg/day intravenously) or after a single dose of cimetidine (50 mg/kg intraarterially). After 30 mg/kg, 27.0% of the metronidazole dose was excreted intact in 24-hr urine and 2.2% in bile. After tinidazole, the recoveries of the intact drug in urine and bile were 48.1% and 1.7%, respectively. After 90 mg/kg, the total recoveries of both drugs were 25-28% smaller than after 30 mg/kg. Phenobarbitone pretreatment did not affect metronidazole levels in plasma but decreased tinidazole levels at 4 hrs. The 24-hr recoveries of the intact nitroimidazoles in urine were significantly reduced by phenobarbitone while the 24-hr bile recoveries were not. Cimetidine treatment enhanced both metronidazole (at 1, 2 and 3 hrs) and tinidazole (only at 1 hr) concentrations in plasma, but this shift was not reflected in the 24-hr urine recoveries of the intact nitroimidazoles. Cimetidine doubled, however, the 24-hr bile recovery of the intact tinidazole. The calculations of the apparent degree of metabolism, assuming no methodological losses, showed that phenobarbitone increased the metabolism of tinidazole by about 62% and that of metronidazole only by about 16%. The effect of a single dose of cimetidine was negligible.

Effect of Single Doses of Cimetidine and Ranitidine on the Steady-State Plasma Levels of Midazolam

H2-Receptor antagonists may interfere with the pharmacokinetics of concomitantly administered drugs. Our study was designed to investigate whether cimetidine or ranitidine influence the disposition and sedative effect of midazolam. The effect of single oral doses of 800 mg cimetidine, 300 mg ranitidine, or placebo on the steady-state concentrations of midazolam was examined in a randomized crossover study in eight healthy subjects. A midazolam steady-state concentration was achieved by an intravenous bolus (0.05 mg/kg)-infusion (0.025 mg/kg/hr) technique. Plasma concentrations of midazolam, cimetidine, and ranitidine and the pharmacodynamic response to midazolam (choice reaction time, sedation index) were monitored throughout the 10-hour infusion. Cimetidine significantly increased the mean (± SD) steady-state plasma concentration of midazolam from 56.7 ± 7.8 to 71.3 ± 19.6 ng/ml (P = 0.004). In contrast, the steady-state midazolam concentration after ranitidine dosing (61.8 ± 6.8 ng/ml) did not differ significantly from that after placebo. No change in choice reaction time or sedation index was detected after cimetidine or ranitidine dosing. Nevertheless, in contrast to ranitidine, the recently advocated once-daily dosing of cimetidine has a potential for hepatic drug interaction that should be considered before its coadministration with drugs that have a narrow therapeutic index. Clinical Pharmacology and Therapeutics (1985) 38, 652–655; doi:10.1038/clpt.1985.240

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.

Changes in bronchial anaphylactic reactivity induced in guinea-pigs by long-term treatment with histamine H2-agents.

Guinea-pigs were sensitized to ovalbumin (OA) by immunization regimens chosen to cause antigen-induced bronchial anaphylactic responses mediated mainly either by IgE-like antibodies or by IgG1-like antibodies. Treatment of the IgE-producing animals for three weeks with the histamine H2-receptor antagonist cimetidine (1 mg kg-1 i.p. once a day) or with the H2-agonist dimaprit (0.1, 1.0, or 10 mg kg-1 i.p. once a day) led to a significantly reduced bronchial response capacity compared with that of the saline-treated controls challenged intravenously with antigen one week after the end of treatment. The changes were biphasic and not strictly dose-dependent. In contrast, acute treatment of immunized animals with a single dose of cimetidine (10 or 30 mg kg-1 i.v.) or dimaprit (1 or 10 mg kg-1 i.v.) 2 min before challenge with OA did not significantly affect the bronchial anaphylactic response. However, long-term treatment with cimetidine (10 mg kg-1) or the dimaprit analogue, S-[4-(N, N-dimethylamino)-butyl] isothiourea (SKF Compound 91488) (1 mg kg-1), which is reported not to activate H2-receptors, had no effect on the response capacity. Treatment with cimetidine (1 mg kg-1) or dimaprit (1 mg kg-1) did not influence the response capacity to antigen challenge in IgG1- type animals. Dimaprit (1 mg kg-1) did not affect the responsiveness to intravenous provocation with histamine in 'IgE-type' animals. Antigen-induced release of histamine from chopped lung tissue in vitro was not significantly affected in 'IgE-type' animals treated with cimetidine (1 mg kg-1) or dimaprit (1 mg kg-1). Treatment of immunized animals with cimetidine or dimaprit one week before and one week after a booster injection of antigen also led to reduced response capacity compared with that of saline-treated controls. However, the serum levels of IgE-like homocytotropic antibodies of these animals were not reduced; on the contrary, those of IgG1-antibody were increased in dimaprit-treated animals. These data show that intermittent treatment with histamine H2-agents reduces reagin-mediated anaphylactic response capacity in vivo in actively sensitized guinea-pigs by an as yet undefined mode of action.

Use of single doses and rapid sampling to detect interactions with cimetidine.

In this study the well-established interaction between cimetidine and theophylline has been demonstrated using only a single dose of cimetidine. Eleven healthy subjects were given a 30 min infusion of theophylline on two separate occasions and plasma levels were monitored at frequent intervals. During one of the studies, a single 400 mg oral dose of cimetidine was given after collection of the 3 h sample. After normalisation of the control and test curves, a deflection was apparent in the test theophylline elimination curve in 9 out of 11 subjects. This method may provide a rapid screening method to detect such interactions.