Effect of bupropion on cimetidine and ranitidine absorption in rats

Cimetidine and ranitidine absorption were studied in rats, alone or in combination with concurrent but separate bupropion oral administration. Blood samples were collected before and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.5, and 6.0 h after dosing. In ranitidine-treated rats, an extra blood sample at 8 h was collected. Assays of cimetidine and ranitidine were carried out using a HPLC method. Mean cimetidine plasma concentrations on concurrent bupropion administration at 0.25 and 0.5 h were approximately 2 and 1.5 times compared to the control. Similarly, mean ranitidine plasma concentrations with bupropion combination at 0.25 and 0.5 h were significantly different and approximately 2 and 3 times higher. Time of maximum concentration for cimetidine and ranitidine on combination were reduced to almost half of the control value. However, only the time of maximum concentration for cimetidine showed statistically significant difference. No significant differences were observed between AUCs, maximum concentrations, and half-lives of cimetidine and ranitidine compared to their respective controls. The results suggest that concurrent bupropion administration may affect the rate but not the extent of absorption of cimetidine and ranitidine.     

Influence of H2 receptor antagonists on the disposition of flurbiprofen enantiomers

The effect of oral cimetidine or ranitidine on the pharmacokinetics of the R and S enantiomers of the nonsteroidal anti-inflammatory drug flurbiprofen and its major metabolite, 4'-hydroxyflurbiprofen, was evaluated. Nine healthy volunteers participated in a randomized crossover design study with the following treatments: (A) flurbiprofen 200 mg; (B) flurbiprofen 200 mg plus ranitidine 150 mg bid for 7 days before and for 2 days after receiving flurbiprofen and (C) flurbiprofen 200 mg plus cimetidine 300 mg qid for 7 days before and for 2 days after receiving flurbiprofen. Blood and urine samples were collected at various intervals during a 48-hour period. These samples were assayed stereospecifically for flurbiprofen and its metabolite. Small but statistically significant differences in the terminal elimination rate constant (K), maximum peak serum drug concentration (Cmax), time to reach peak concentration (tmax), oral clearance (Cl/F) and area under the curve (AUC) were noted for flurbiprofen enantiomers. No significant treatment*isomer interactions were observed, indicating that neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen. Cimetidine, but not ranitidine, resulted in small (less than or equal to 15%) but statistically significant changes in flurbiprofen pharmacokinetic parameters. The interaction between H2-antagonists and flurbiprofen is unlikely to be clinically important.     

Comparative effects of H2-receptor antagonists on drug interaction in rats

The most widely used H2-receptor antagonist, cimetidine, is known to interact with cytochrome P-450 drug-metabolizing enzymes and, therefore, interacts with other drugs which may be administered concurrently. In this study, effects of three H2-receptor antagonists, famotidine, ranitidine, and L-643,441, on drug interaction were studied using cimetidine as a positive control. Cimetidine and L-643,441, but not famotidine or ranitidine, prolonged antipyrine elimination and hexobarbital-induced sleeping time. The effect of cimetidine and famotidine on the anticoagulant effect on warfarin in rats was also investigated. Pretreatment of rats with cimetidine produced a significant depression of plasma prothrombin complex activity, whereas concomitant administration of famotidine did not alter the plasma prothrombin complex activity. Whereas cimetidine is known to impair the elimination of a number of drugs metabolized by microsomal mixed function oxidase enzyme systems, the results of the present study suggest that famotidine and ranitidine have little effect on these enzyme systems.     

西咪替丁对戊巴比妥睡眠时间的影响

腹腔内一次注射476μmol/kg西咪替丁,雌雄小鼠和大鼠的戊巴比妥睡眠时间分别延长102%、127%和43%、119%(P<0.01);等摩尔雷尼替丁对上述动物PST无明显影响。多次poCD476μmol/kg,雄性大鼠PST延长81%(P<0.01),相同条件下RD对PST亦无明显影响。并发现多次poCD后,其戊巴比妥血浓度与PST呈正相关。并初步探讨了CD延长PST的机理。     

A comparative study of the effects of ranitidine and cimetidine on carbohydrate tolerance, growth hormone secretion and the hypothalamic-pituitary-gonadal axis in man

The effect of chronic oral administration of cimetidine (1 g per day) and ranitidine (300 mg per day) on plasma levels of prolactin (PRL), testosterone, dihydrotestosterone (DHT), luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG) and human growth hormone was compared in 2 groups of male patients who presented with dyspeptic symptoms. Eight were treated with ranitidine and 9 with cimetidine for 4 weeks. The glucose and insulin response to a 100 g oral glucose load was also assessed. Cimetidine treatment resulted in a significant increase in plasma testosterone levels which was not found in the ranitidine group. No significant change occurred in PRL, LH, FSH, SHBG, DHT and growth hormone. There was no evidence of a significant alteration in carbohydrate metabolism.     

Effect of a short-term oral administration of cimetidine and ranitidine on the basal and thyrotropin-releasing hormone-stimulated serum concentrations of prolactin, thyrotropin and thyroid hormones in healthy volunteers. A double-blind cross-over study

Cimetidine (400 mg b.d.), ranitidine (150 mg b.d.) and placebo were administered for 1 week to 6 healthy male volunteers in a randomized double-blind cross-over fashion. Hormonal concentrations before and after a TRH test were assessed before and after each treatment. A spontaneous decrease in the hormonal response to TRH was observed after placebo treatment. Both cimetidine and ranitidine induced a significant increase in basal prolactin (PRL) values. Neither TSH nor T3 were modified by cimetidine or by ranitidine. The basal concentration of reverse T3 was increased during cimetidine treatment. There was a significant rise in post-TRH T4 after cimetidine and ranitidine administration. These results suggest a role for histamine H2 receptors in the secretion of PRL and T4. Moreover, cimetidine affects the hepatic metabolism of thyroid hormones.     

Comparison between ranitidine and cimetidine in the short-term treatment of duodenal ulcer

Two groups of 46 and 49 patients each with endoscopically proved duodenal ulcer and not previously treated, received ranitidine (150 mg X 2 daily) and cimetidine (1 g/day) respectively for eight weeks. The disappearance of the ulcer was observed endoscopically in 78% of both the first and second groups of patients. Of the ten patients non-responders to ranitidine, six were treated again for eight weeks with ranitidine and four with cimetidine for eight weeks; all of them recovered completely apart from one of the cimetidine treated patients. Of the 11 patients non-responders to cimetidine, seven were retreated with cimetidine and 4 with ranitidine for a further eight weeks and all of them obtained a complete recovery except for one of the cimetidine treated patients. No relevant side-effects were observed with either drug. In conclusion cimetidine and ranitidine showed a comparable therapeutic value.     

The effect of cimetidine and ranitidine on paracetamol glucuronidation and sulphation in cultured rat hepatocytes

Cimetidine and ranitidine have been investigated for their ability to inhibit conjugation reactions in cultures of rat hepatocytes. Neither compound had any appreciable effect on rates of paracetamol sulphation. However, both cimetidine and ranitidine inhibited the glucuronidation of paracetamol in a dose-dependent manner. No adverse effects on cellular viability were noted utilizing enzyme leakage (lactic dehydrogenase) or protein synthesis measurements. The kinetics of inhibition by ranitidine were studied in more detail. At 0.25 mM ranitidine, the inhibition appeared to be purely competitive. However, at higher concentrations decreases in Vappmax were noted suggesting a more complex mechanism of inhibition. The relevance to inhibition in vivo by cimetidine and ranitidine and possible interactions between paracetamol and these histamine H2-receptor antagonists are discussed.     

Effects of ranitidine, a new histamine H2-receptor antagonist, on secretagogue-stimulated gastric secretion in rats: comparison with cimetidine (author's transl)

Antisecretory effects of ranitidine on secretagogue-stimulated gastric secretion in acute fistula rats were studied. Histamine 2HCl (8 mg/kg/hr), pentagastrin (125 micrograms/kg/hr) or carbachol (128 micrograms/kg/hr) was continuously given i.v. by an infusion pump, through the tail vein to acute fistula rats. Gastric secretion was collected hourly for 5 hr and analyzed for its components. Cimetidine was used as a reference drug. Both drugs were given i.v. by a bolus injection in the tail vein 30 min after the injection of each stimulant. Both ranitidine (1 and 10 mg/kg) and cimetidine (10 and 60 mg/kg) significantly (P less than 0.05) inhibited the histamine-stimulated gastric secretion (volume, acid and pepsin output) for 1 to 4 hr. Both ranitidine (10 mg/kg) and cimetidine (60 mg/kg) significantly (P less than 0.05) inhibited the pentagastrin-stimulated gastric secretion for 2 to 3 hr. both ranitidine (10 mg/kg) and cimetidine (10 and 60 mg/kg) markedly inhibited the gastric acid secretion in response to carbachol. However, cimetidine (10 or 60 mg/kg) significantly (P less than 0.05) stimulated the volume and pepsin output by carbachol. We conclude that ranitidine is about 6 times more potent than cimetidine for histamine- or pentagastrin-stimulated gastric secretion and almost equal to cimetidine for carbachol-stimulated gastric acid output in rats.     

Effect of histamine H2-receptor antagonists on DNA synthesis in adult rat hepatocytes in primary culture. Cimetidine enhanced hepatocytes proliferation stimulated with insulin and epidermal growth factor

The effects of three of the most widely used histamine H2-receptor antagonists, cimetidine, ranitidine and famotidine, on liver cell growth were studied in vitro using adult rat hepatocytes in primary culture, because these antagonists are commonly given to patients with hepatic cirrhosis or fulminant hepatic failure for protection against peptic ulcers and gastrointestinal hemorrhage. At their clinically effective concentrations in the blood (0.5-5 micrograms/ml cimetidine, 0.25-2.5 micrograms/ml ranitidine and 0.05-0.5 microgram/ml famotidine), these three antagonists did not have any effect on replicative DNA synthesis either in the presence or absence of insulin plus epidermal growth factor (EGF). However, unexpectedly DNA synthesis stimulated by insulin and EGF was found to be enhanced by 0.05-0.5 mg/ml cimetidine, although it was unaffected or inhibited by ranitidine and famotidine at the concentrations tested. Cimetidine caused maximal enhancement of 1.5-2 times the control level of DNA synthesis at a concentration of 0.25 mg/ml. Cimetidine also had an enhancing effect at submaximal concentrations of insulin and EGF, but neither cimetidine nor the other antagonists had any stimulatory effect on DNA synthesis in the absence of insulin plus EGF. This enhancement of DNA synthesis by cimetidine resulted in significant increase in the total DNA content of the hepatocytes in culture. Under the conditions used, cimetidine had the lowest toxicity of these three antagonists and ranitidine the highest, as judged from data on DNA synthesis and the total protein content of cultured hepatocytes, leakage of aminotransferases from the cells and morphological observations.     

Different effects of cimetidine and ranitidine on gastric emptying in rats and man

Cimetidine and ranitidine were tested for their effect on gastric emptying in the rat. At low doses, cimetidine was inactive, whereas it significantly delayed emptying rate when administered at higher doses. Ranitidine always accelerated gastric emptying. At variance with rats, ranitidine delayed human gastric emptying whereas cimetidine was completely inactive. All these data are consistent with the idea that these effects of H2-antagonists are independent of H2-receptor blockade.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Single oral doses of cimetidine (400 mg), ranitidine (150 mg), promethazine (25 mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor of the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

Effect of cimetidine or ranitidine pretreatment on hepatic mixed function oxidase activity in the rat

This study compared the effect of single equimolar oral doses of cimetidine (100 mg/kg) or ranitidine (139 mg/kg) on rat hepatic mixed function oxidases. Cimetidine significantly (p less than 0.05) increased hexobarbital sleeping time and prolonged aminopyrine and theophylline elimination. In contrast, ranitidine did not significantly affect hexobarbital sleeping time and theophylline elimination but significantly (p less than 0.025) increased aminopyrine elimination. Aminopyrine N-demethylase activity in vitro was significantly (p less than 0.05) inhibited by cimetidine pretreatment but significantly (p less than 0.025) increased by ranitidine pretreatment. The direct addition of cimetidine or SKF 525A to the 10,000g supernatant fraction from controlled liver homogenates decreased aminopyrine N-demethylase activity, whereas the direct addition of ranitidine tended to increase aminopyrine N-demethylase activity. A significant correlation (r = 0.65, p less than or equal to 0.005) was observed between hexobarbital sleeping time in vivo and aminopyrine N-demethylase activity in vitro in the same rat. The results of this study showed that cimetidine inhibited mixed function oxidases, whereas ranitidine had no effect or tended to stimulate mixed function oxidases.     

Effects of H2-receptor antagonists on plasma aldosterone response to angiotensin II in healthy subjects; (II). Comparison of cimetidine and ranitidine

The effects of H2-receptor antagonists, cimetidine and ranitidine, on plasma aldosterone response to angiotensin II (AII) were examined in six healthy subjects. The study was carried out on three different occasions with a two week interval. Cimetidine (400 mg), ranitidine (150 mg) or a placebo was given orally every 12 hours for 3 days in a double-blind, cross-over, double-dummy design. On the fourth day, 1 hour after the final (seventh) administration of the same agent, furosemide (20 mg) was injected intravenously. The plasma levels of renin activity (PRA), AII and aldosterone (PA) were determined for a 120 minute period after furosemide. PRA, AII and PA increased after furosemide with as well as without H2-receptor antagonist. The basal and stimulated levels of these parameters were not significantly different at any observation point among the three regimen groups. A significant correlation was observed between AII and PA with placebo (P less than 0.01) and ranitidine (P less than 0.01), but not with cimetidine (P greater than 0.05). The slope of the regression line with ranitidine was not significantly different from that of the placebo. These data indicate that the PA response to AII is blunted by cimetidine, but not by ranitidine. The current study supports the idea that this blunted response during cimetidine is independent of the blockade of H2-receptor.     

CIMETIDINE AND RANITIDINE: A STUDY OF COMPETITIVE AND ION-CHANNEL BLOCKADE IN THE TOAD ISOLATED RECTUS ABDOMINIS MUSCLE

Responses of the toad isolated rectus abdominis muscle to cumulative doses of carbachol were recorded in the absence or presence of varying concentrations of cimetidine or ranitidine. The corresponding cumulative log concentration-response curves for carbachol were then plotted for each antagonist studied. Cimetidine (1 mmol/l) produced a straight and parallel 1.8-fold shift of the carbachol curve to the right of the corresponding control curve with no significant change in the maximal response. Cimetidine, at doses of 2.5 mmol/l and 5 mmol/l, and ranitidine, at doses of 0.1 mmol/l, 0.25 mmol/l and 0.5 mmol/l, produced a concentration-dependent and non-parallel shift of the carbachol curve to the right of the corresponding control curve accompanied by a marked decline of maximal responses. The results provide further evidence that ion-channel block may be involved in the neuromuscular blockade produced by cimetidine or ranitidine, the latter being more potent in this respect. Competitive antagonism may also be partly responsible for cimetidine-induced neuromuscular blockade, especially at lower drug concentrations.     

Differential effects of cimetidine and ranitidine on imipramine demethylation and desmethylimipramine hydroxylation by human liver microsomes

Summary The effect of cimetidine and ranitidine on the demethylation of imipramine (IMI) and on the hydroxylation of desmethylimipramine (DMI) was studied in microsomes from four human livers. Cimetidine inhibited both demethylation of IMI and 2-hydroxylation of DMI, whilst the effect of ranitidine was not statistically significant. 2-hydroxylation of DMI is probably mediated by debrisoquine hydroxylase, a cytochrome P-450 isozyme that is monogenically controlled. The results suggest that cimetidine inhibits this enzyme.     

Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics

Summary The pharmacokinetics of a single oral dose (400 mg) of carbamazepine and sodium valproate were compared in peptic ulcer patients before and after four weeks of a therapeutic course of either cimetidine (1 g/day, n=6 subjects) or ranitidine (300 mg/day, n=6 subjects). There was a small (up to 20%) but statistically significant decrease in oral clearance of carbamazepine after cimetidine treatment. A similar fall in sodium valproate clearance in five cimetidine-treated patients was accompanied by a significantly prolonged elimination half-life. No such trends were demonstrated during ranitidine treatment. Since both anticonvulsants are partly metabolized by hepatic mixed function oxidases, an inhibition by cimetidine at this level may be responsible for the observed impairment of clearance. Thus a potentially important clinical interaction may occur in patients taking anticonvulsants and cimetidine concurrently.     

The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine or high dose ranitidine.

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/- s.d. values of AUC were 105 +/- 40 micrograms l-1 for placebo treatment, 111 +/- 45 micrograms l-1 h for ranitidine and 211 +/- 64 micrograms l-1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/- 14, 39 +/- 27 and 76 +/- 40 micrograms l-1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Summary

Single oral doses of cimetidine (400?mg), ranitidine (150?mg), promethazine (25?mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor or the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

Pharmacokinetics of cimetidine in critically ill patients

Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p<0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.