The effect of cimetidine on the pharmacodynamics of theophylline-induced seizures and ethanol hypnotic activity.

Due to its availability as an over-the-counter drug, the use of cimetidine is increasing, thus adverse interactions with other commonly used agents may also increase. The aim of this study was to investigate whether acute administration of cimetidine could alter the pharmacodynamics of theophylline neurotoxicity and the hypnotic action of ethanol.To examine these questions, rats received a dose of 77 mg/kg cimetidine followed by a constant infusion of either theophylline (1.2 mg/min.) or ethanol (16.3 mg/min.) until the onset of the pharmacological end point, maximal seizure or loss of righting reflex, where samples of blood and brain were obtained and assayed for either theophylline or ethanol. We report that cimetidine in doses that may cause pharmacokinetic interactions did not affect the concentration-effect relationship of either the stimulating action of theophylline or the depressant activity of ethanol. These outcomes emphasize the relative safety which patients using cimetidine in self-medication rely on.     

Effect of grapefruit juice on drug metabolism in rats

The effect of grapefruit juice on in vivo drug metabolism was investigated in rats. The juice (4 ml or 8 ml/kg) was given orally once daily for 2 consecutive days and its effect on theophylline metabolism, pentobarbitone sleeping time and the tremorgenic action of tremorine was studied. The effect of grapefruit juice on some of these parameters was compared with that of the known drug metabolism inhibitor cimetidine given ip. Grapefruit juice at 4 ml and 8 ml/kg produced significant increases in pentobarbitone sleeping time that reached 46 and 79%, respectively, compared with 107% produced by cimetidine (50 mg/kg, ip). The juice at 4 ml/kg also significantly increased plasma theophylline concentration when measured 15, 30, 60 and 90 min after ip theophylline administration (10 mg/kg). Thereafter, no significant differences were detected in plasma drug concentrations between juice- and saline-treated animals. Administration of tremorine (25 mg/kg, ip) to saline-treated controls produced, within 2 or 3 min, tremors, piloerection, profuse salivation, defaecation, urination and chromodacryorrhesis (red tears). The onset of appearance of these signs was delayed to about 7 min in rats pretreated 1 hr earlier with either grapefruit juice (4 ml/kg, orally) or cimetidine (50 mg/kg, ip). The severity of the above signs was markedly reduced to a similar extent in both the juice- and cimetidine-treated rats. These results suggest that grapefruit juice may act as an inhibitor of drug metabolism in rats, and that its consumption may alter the disposition of certain concomitantly administered drugs.     

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

Summary 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.     

Effect of histamine receptor antagonists on aminophylline-induced seizures and lethality in mice

The aim of this study was to evaluate the effects of H(1) (antazoline and astemizole) or H(2) (cimetidine and famotidine) histamine receptor antagonists on the clonic phase, tonic seizures and morality of mice challenged with aminophylline to induce convulsions in mice. Moreover, the total plasma and brain concentrations of theophylline were evaluated. Astemizole (1 mg/kg) did not affect the threshold for aminophylline-induced seizures, but when administered at a dose of 2 mg/kg, it significantly reduced the CD(50) value of aminophylline from 249 mg/kg to 211 mg/kg (p < 0.01). The remaining histamine receptor antagonists studied i.e., antazoline (up to 1 mg/kg), cimetidine (up to 40 mg/kg) and famotidine (up to 10 mg/kg) had no impact on seizure susceptibility in aminophylline-induced convulsions. Furthermore, astemizole (2 mg/kg) decreased latency to the clonic phase of aminophylline-induced convulsions from 51.1 +/- 4.5 to 32.1 +/- 4.3 min (p < 0.01). It is noteworthy that astemizole, a novel H(1) receptor antagonist, did not alter the brain and plasma levels of theophylline, so the existence of pharmacokinetic interactions was excluded. Our results indicate that some interactions between methylxanthines and histamine receptor antagonists may be clinically important since these drugs are usually combined during the treatment of status asthmaticus.     

Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

1 The effect of concurrent cimetidine administration on the disposition of theophylline was investigated in eight male patients (56-78 years) with chronic obstructive pulmonary disease (COPD). 2 The patients, who were taking oral theophylline preparations chronically (384-1020 mg/day), received a [15N], [13C]-labelled analogue of theophylline (10 mg i.v.) before and during cimetidine treatment (1200 mg/day p.o.). 3 During cimetidine treatment trough levels of theophylline increased 34% (6.4 +/- 0.8 to 8.6 +/- 1.0 micrograms/ml, P less than 0.05), half-life increased 48% (6.5 +/- 0.6 to 9.6 +/- 0.8 h, P less than 0.001), and total plasma clearance decreased 33% (3.88 +/- 0.46 to 2.59 +/- 0.33 l/h, P less than 0.001), without a significant change in volume of distribution or protein binding. 4 The effect of cimetidine on plasma levels of theophylline was maximal within 72 h. Levels returned to control values within 48 h after its discontinuation. 5 Although there was no correlation with mean plasma concentrations of cimetidine, the change in clearance of theophylline correlated with initial clearance values (r = 0.72). 6 Cimetidine reduced the plasma clearance of theophylline in patients with COPD to an extent similar to that reported in healthy volunteers.     

The interaction of cimetidine with various antihypertensive agents in the spontaneously hypertensive rat

The H2-receptor antagonist cimetidine (250 micrograms) administered intracerebroventricularly (i.c.v.) 15 and 30 min before clonidine (25 micrograms kg-1 i.v.), significantly antagonized clonidine-induced hypotension in anaesthetized spontaneously hypertensive rats. The hypertensive response of cimetidine was correlated with the inhibition of clonidine-induced hypotension. In addition, cimetidine (250 micrograms i.c.v.) counteracted the hypotensive effects of pentolinium (5.0 mg kg-1 i.v.), guanethidine (5.0 mg kg-1 i.v.) and minoxidil (1.0 mg kg-1 i.v.) These data do not support previous suggestions that the hypotensive action of clonidine is caused by stimulation of the H2-receptor, but suggest that central administration of cimetidine causes peripheral vasoconstriction and this may offer resistance to the hypotensive action of different antihypertensive agents.     

Effects of exposure to standard- and nicotine-reduced-cigarette smoke on pharmacokinetics of theophylline and cimetidine in rats.

Influences of exposure to standard- (containing nicotine and tar) and nicotine-reduced-cigarette smoke on the pharmacokinetics of theophylline (20 mg/kg, per os) and cimetidine (50 mg/kg, per os) were investigated in rats. Animals were exposed to standard- or nicotine-reduced-cigarette smoke for 8 min with a "smoking machine". In control rats, theophylline concentrations in plasma increased rapidly, peaked 2 h later, and then decreased gradually. Concentrations of theophylline in plasma of rats exposed to standard- and nicotine-reduced-cigarette smoke were suppressed in comparison with that of control rats, and the suppressive effect of nicotine-reduced-cigarette smoke was weaker than that of standard-cigarette smoke. The suppression of theophylline concentrations in plasma induced by exposure to cigarette smoke may be due to nicotine and other constituents of the cigarette smoke, even if the effects are slight. For cimetidine, no difference was found between drug concentration in plasma of rats exposed to nicotine-reduced-cigarette smoke and that of control rats; however, the drug concentration in plasma of rats exposed to standard-cigarette smoke was markedly suppressed. These results suggest that the suppression of cimetidine concentrations in plasma may be due solely to nicotine in cigarette smoke.     

Verapamil worsens ethanol-induced gastric ulcers in rats

The effect of verapamil on ethanol-induced gastric ulceration was investigated in rats. Orally administered ethanol (0.5 ml), 10, 20 or 40% v/v, dose dependently produced glandular lesions, ranging from petechiae to haemorrhagic ulcers. These lesions were worsened by verapamil (2, 4 or 8 mg/kg given intraperitoneally (i.p.) 30 min beforehand) in the 30 min and 2 h ethanol-exposure experiments. However, ethanol ulceration or its aggravation by verapamil was antagonised by calcium gluconate (112 or 224 mg/kg given per os (p.o.) 30 min before ethanol administration) in a dose-related manner. These findings suggest that intracellular calcium depletion in the gastric glandular mucosa may account for ethanol ulceration and the ulcer-aggravating action of verapamil.     

The Effect of Immunosuppression by Total-Body Irradiation on the Pharmacodynamics of Centrally Active Drugs in Rats

The aim of this investigation was to assess whether immunosuppression induced by total-body irradiation (TBI) affects the pharmacodynamics of centrally acting drugs. Female Sabra rats were exposed to a single dose of gamma irradiation (5.3 Gy). Four days later, when both the cellular and the humoral immune responses were impaired, they received an i.v. infusion of either phenobarbital (0.8 mg/min), ethanol (16.3 mg/min), pentylenetetrazol (PTZ; 0.618 mg/min), or theophylline (as aminophylline; 2 mg/min). The infusion was stopped at the onset of the pharmacologic end point—loss of righting reflex for the depressant agents or maximal seizures for the stimulant drugs—and the concentrations of the neuroactive drugs at that point were determined. In the ethanol experiment, blood samples were also taken upon awakening. The radiation-induced immunosuppression significantly decreased the CNS sensitivity to the depressant action of both phenobarbital and ethanol as indicated by the higher CSF phenobarbital concentrations required to induce sleep in the irradiated rats versus controls (156±4 vs 133 ±5 mg/L, respectively; P < 0.05), and the higher serum ethanol concentrations at the onset and offset of sleep in the immunosuppressed group versus control values (4.6±0.2 and 1.68±0.01 vs 3.79±0.17 and 1.32±0.9 mg/mL, respectively; P < 0.04). Exposure to TBI did not alter the pharmacodynamics of the two convulsant drugs (theophylline andPTZ).     

Effect of cimetidine and ranitidine on plasma theophylline in patients with chronic obstructive airways disease treated with theophylline and corticosteroids

Summary Thirty adults with chronic obstructive airways disease, who were stabilised on theophylline and corticosteroids, took part in a single blind study of the effects of cimetidine and ranitidine on plasma theophylline concentrations. The patients were randomised to receive either 150 mg ranitidine b. d. or 400 mg cimetidine b. d. for one week and serial plasma theophylline measurements were made over a 12-hour period on two consecutive days before, during and after treatment with the H₂-antagonist.There was a significant increase in plasma theophylline during treatment with cimetidine; two patients had levels > 20 mg·1^–1. The average increase in the theophylline concentration due to cimetidine was 32%. There was no significant change in plasma theophylline during ranitidine administration. No adverse effect occurred in any patient during the study.     

The effects of once-daily dosing with ranitidine and cimetidine on theophylline pharmacokinetics

Twelve healthy non-smokers (7M and 5F) completed a balanced three-way crossover investigation designed to characterise the influence of oral cimetidine (800 mg), ranitidine (300 mg) and placebo pretreatment for 7 days on the pharmacokinetics of a 250 mg single oral dose of theophylline. The oral clearance of theophylline after ranitidine pretreatment, 4.55 +/- 1.69 l/h (mean +/- SD) was indistinguishable from that after placebo, 4.78 +/- 1.96 l/h, but cimetidine was associated with a significant 21% reduction in theophylline clearance, 3.58 +/- 1.07 l/h (P = 0.006). There was a correspondingly significant increase in the terminal half-life of theophylline following cimetidine, 6.11 +/- 1.29 h (P = 0.017), compared with 5.05 +/- 1.43 h and 4.88 +/- 1.45 h for placebo and ranitidine, respectively. There was no change in maximum theophylline concentration or time to maximum but following cimetidine the plasma theophylline levels between 4 and 12 hours were 15-50% higher than following placebo (P less than 0.002). These data indicate a significant interaction between 800 mg cimetidine given once daily and theophylline which is likely to be the result of enzyme inhibition. Once-daily dosing with 300 mg ranitidine had no significant effect on theophylline pharmacokinetics.     

Naloxone-induced increase in blood and brain ethanol concentrations in rats

Although a reduction in blood ethanol concentration has been proposed to mediate the ethanol antagonist activity of naloxone observed in clinical and experimental situations, an increase in this variable as well as in brain ethanol concentration has been found in rats treated with naloxone (0.5 and 2.0 mg/kg, i.p.) ten min after intragastric administration of ethanol (1 and 2 g/kg). This effect disappeared either when naloxone was administered 50 min after ethanol or when ethanol was given intraperitoneally. On the other hand, naloxone induced a slight but significant slowing in intestinal transit rate. These results suggest that naloxone may facilitate gastrointestinal absorption of ethanol when administered soon after an oral load of this drug. Therefore, mechanisms other than a pharmacokinetic interaction appear to be involved in the antagonist action of naloxone.     

Lack of Effect of Olanzapine on the Pharmacokinetics of a Single Aminophylline Dose in Healthy Men

Study Objective . To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. Design . Two-way, randomized, crossover study. Setting . Clinical research laboratory. Subjects . Nineteen healthy males (16 smokers, 3 nonsmokers). Interventions . Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. Measurements and Main Results . Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4′-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. Conclusion . As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.     

The influence of intravenous cimetidine dosage regimens on the disposition of theophylline

The influence of the method of cimetidine administration on theophylline disposition was studied in nine healthy, cigarette smoking male volunteers. The treatment phases consisted of: A) theophylline alone, B) theophylline plus intermittent cimetidine therapy (300 mg IV every 6 hr), and C) theophylline in combination with continuous infusion cimetidine (50 mg/hr). Theophylline (4.8 mg/kg) was administered intravenously as aminophylline over 30 minutes during each treatment phase. During study phases B and C subjects received 48 hours of cimetidine therapy beginning 24 hours prior to theophylline dosing. Blood samples for determination of theophylline concentrations were collected serially over 24 hours. Serum theophylline concentrations were determined in duplicate using fluorescence polarization immunoassay (Abbott Diagnostic TDx). The average age of the subjects was 27.4 +/- 4.7 years, and the individual smoking histories ranged from 0.5 to 1.5 packs per day (average 0.89 +/- 0.33). The mean (+/- SD) body weight was 79.1 +/- 8.2 kg and all subjects were within 20% of their ideal body weight. Theophylline pharmacokinetic parameters were determined using noncompartmental analysis. ANOVA for repeated measures and Tukey's multiple comparison test were used for statistical analysis. The mean (+/- SD) theophylline clearance for each of the treatment groups was: 1.4 +/- 0.4, 1.2 +/- 0.3, and 1.2 +/- 0.2 ml/min/kg for phases A, B and C, respectively. Cimetidine decreased the clearance of theophylline, however, theophylline clearance was not statistically different between regimens B and C. Thus, the method of cimetidine administration (intermittent versus continuous infusion) did not influence the magnitude of the drug-drug interaction.     

Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats

Theophylline, widely used in the treatment of pulmonary diseases, has a narrow therapeutic index; the recommended plasma levels being 10–20 μg/ml in humans. The misuse or abuse of theophylline can cause life-threatening central nervous system and cardiovascular effects. Increased intracellular Ca²⁺ levels are thought to play an important role in theophylline toxicity and death. The objective of this study was to determine whether Ca²⁺ channel blockers, e.g. verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0 mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats were observed for toxic signs and survival over a period of 15 days. All three calcium channel blockers significantly reduced the theophylline-induced sudden death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and sudden death. Our results support previously reported findings that calcium plays a major role in theophylline-induced toxicity and death.     

The vascular and glandular organoprotective properties of metronidazole in the rodent stomach

Background : The gastroprotective action of metronidazole, an antimicrobial used in the therapy against Helicobacter pylori infection, is unclear. Thus, the aim of the present investigation was to study the organoprotective action and antiulcer mechanisms of this drug in rodents.
Methods and results : Metronidazole (10 mg/kg), given either per os or intraperitoneally, 30 min beforehand, reduced ethanol (40%, 10 mL/kg, p.o.)-induced gastric mucosal damage in male rats. Likewise, oral administration of metronidazole dose-dependently attenuated the indomethacin (30 mg/kg, p.o.)-induced gastric lesion formation and the concurrent depletion of mucosal mucus. However, metronidazole did not affect the basal mucosal prostaglandin E₂ content. In an ex vivo gastric chamber preparation, 40% ethanol incubation markedly lowered transmucosal potential difference and increased mucosal vascular permeability in rat stomachs. Incubation with all doses of metronidazole did not modulate gastric mucosal blood flow nor transmucosal potential difference, either before or after ethanol treatment. Nevertheless, the increase in vascular permeability by 40% ethanol was significantly alleviated by either p.o. or i.p. metronidazole pre-treatment. In addition, exposure of the isolated rabbit gastric gland preparation to metronidazole (10⁻⁵ and 10⁻⁴  m ) significantly attenuated the damaging action of 10% ethanol.
Conclusion : It is concluded that metronidazole possesses a direct vascular and glandular organoprotective property in the rodent stomach. However, the anti-ulcer action does not appear to involve prostaglandins nor act through the improvement of gastric mucosal blood flow. Preservation of intramucosal mucus may partly contribute to the prevention of indomethacin-induced ulceration in rats.     

Behavioral interactions of ethanol and methylxanthines

The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.     

Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats

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.     

Interspecies Scaling of Cimetidine–Theophylline Pharmacokinetic Interaction: Interspecies Scaling in Pharmacokinetic Interactions

The aim of the present study was the use of an interspecies scaling approach to predict drug interactions during preclinical drug disposition studies. Theophylline and cimetidine were selected because of their documented interaction. The literature was searched for pharmacokinetic data of intravenously administered theophylline alone and in the presence of cimetidine in humans, dogs and rats. Further, we determined the theophylline-cimetidine drug interaction in rabbits. Application of allometric equations to the pharmacokinetic parameters and the conversion of chronological time into pharmacokinetic time allowed us to obtain the complex Dedrick plot for theophylline when administered alone or in combination with cimetidine. A superimposable kinetic profile was obtained for the plasma levels of theophylline in all species studied, both with and without cimetidine. From the terminal phase of the curves it is possible to calculate the elimination half-life: 2.69 apolisychrons for theophylline when it is administered alone and 3.86 apolisychrons when it is administered in combination with cimetidine. This 43% increase in t_1/2 is similar to the increase in the elimination half-life of theophylline in humans when it is administered after pretreatment with cimetidine. These results show that an interspecies scaling approach may be useful to predict the effect of interactions in humans from the results obtained in preclinical research with new drugs.     

Ranitidine, cimetidine, famotidine have no effect on post-prandial absorption of ethanol 0.8 g/kg taken after an evening meal

Forty-seven healthy male subjects were studied twice using a randomized, placebo-controlled design. Each subject took an 8-day course of two of the following four regimens; 300 mg ranitidine, 800 mg cimetidine, 40 mg famotidine or placebo (identical either to 300 mg ranitidine or 800 mg cimetidine). The systemic bioavailability of ethanol (integrated 6-h plasma ethanol concentration, peak plasma ethanol concentration, and the time to peak plasma ethanol concentration) was measured after the oral ingestion of 0.8 g of ethanol per kg body weight, given one hour after an evening meal on Day 8 of each regimen. There was no significant difference of integrated 6-h plasma ethanol concentration, peak ethanol concentration, or time to reach peak ethanol concentration after dosing with either ranitidine, cimetidine or famotidine or placebo.