The effect of food and antacid on the absorption of fendosal

Fendosal (200 mg) was given orally to each of two separate groups of twelve healthy male volunteers on separate occasions to assess the influence of food or antacid on the bioavailability of fendosal. Blood samples (20 ml) were drawn during 12 hours post-dosing and fendosal plasma concentrations were quantitated by a validated fluorescence technique. Food was shown to have no significant effect (p greater than 0.05) on fendosal bioavailability. However, the bioavailability of fendosal in the presence of an antacid was reduced by 80 per cent. In vitro studies suggested that a complexation between unionized fendosal and the metal ions contained in the antacid may be responsible for the decrease in the rate and extent of absorption observed in vivo.     

The effect of antacid and cimetidine on the oral absorption of the antifungal agent SCH 39304

The single-dose pharmacokinetics of the antifungal agent SCH 39304 (Schering-Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effect on any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304, as assessed by the area under the plasma concentration-time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC0-1 for the drug given alone was 80.5 +/- 15.8 micrograms.hr/mL, compared to 81.4 +/- 12.7 and 79.7 +/- 9.6 micrograms.hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae0-1) was 22.7 +/- 5.1, 24.2 +/- 9.2, and 23.6 +/- 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the tmax in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmacokinetic disposition of single-dose SCH 39304.     

The effects of antacid and propantheline on the absorption of oral ranitidine

The effects of propantheline bromide and an aluminum hydroxide/magnesium hydroxide suspension on absorption of ranitidine were evaluated in 12 healthy volunteers according to a Latin square design. Ranitidine 150 mg was administered alone, with 30 ml antacid or preceded by 15 mg propantheline. Ten serum samples were obtained over 12 hours during each treatment period for measurement of ranitidine concentration. The antacid had no significant effect on ranitidine absorption, but propantheline increased the relative bioavailability of ranitidine by 22%. In addition, there was a trend, although not statistically significant, for propantheline to increase the maximum ranitidine serum concentration and the time to maximum serum concentration. Ranitidine can be administered concomitantly with the evaluated doses of antacid and propantheline without a clinically significant alteration in its absorption.     

The effect of ranitidine, cimetidine or famotidine on low-dose post-prandial alcohol absorption

Plasma alcohol concentration following oral ingestion of 0.3 g/kg of alcohol (ethyl alcohol), one hour after an evening meal, was measured in four groups of 12 healthy subjects. Each group had a control study and a repeat study after 7 days dosing with either placebo or an H2-receptor antagonist (300 mg ranitidine nocte, 800 mg cimetidine nocte, or 40 mg famotidine nocte). There was no significant difference between the control and post-dosing studies in the integrated 4-h plasma alcohol concentration, peak plasma alcohol concentration, or time to reach peak alcohol concentration. This study shows that post-prandial alcohol absorption after 0.3 g/kg of alcohol is not affected by ranitidine, cimetidine or famotidine.     

The effect of antacid and ranitidine on droxicam pharmacokinetics.

Droxicam is a nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of concomitant administration of antacid or ranitidine on droxicam pharmacokinetics has been investigated. On three separate phases, 15 healthy volunteers received a single oral 20-mg dose of droxicam either alone, with antacid (400 mg aluminum hydroxide + 400 mg magnesium hydroxide, three times/day), or with ranitidine (300 mg, two times/day) for 6 days. Piroxicam, the active substance from droxicam, was quantified by high-performance liquid chromatography. The pharmacokinetic parameters for droxicam given alone were: maximum peak plasma concentration (Cmax) = 1.53 +/- .21 micrograms/mL (mean +/- SD), time to peak concentration (Tmax) = 7.5 +/- 2.1 hr, t1/2a = 1.38 +/- .82 hour, t1/2el = 53.3 +/- 11.9 hr, Cl/F = 2.98 +/- .71 mL/min, volume of distribution (Vd/F) = 13.2 +/- 1.8 L and area under the curve (AUC) = 117.6 +/- 26.8 micrograms/hour/mL. The subject effect was significant for all the pharmacokinetic parameters except for the absorption half-life (P < .05). Concomitant antacid or ranitidine administration had no significant effect on any of the droxicam pharmacokinetic parameters. The results of this study suggest that antacid or ranitidine do not significantly alter the oral absorption or pharmacokinetic disposition of single-dose droxicam.     

The effect of ranitidine and cimetidine on imipramine disposition

Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t_1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml^–1) or ranitidine (1.14 µg·h·ml^–1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.     

The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics

The effects of two histamine 2-receptor antagonists, cimetidine and ranitidine, on the single-dose pharmacokinetics of diltiazem were studied in 6 healthy subjects. A single 60-mg oral dose of diltiazem was administered alone, after ranitidine 150 mg twice daily for 7 days, and after cimetidine 300 mg 4 times a day for 7 days. Plasma samples were obtained over a 10-hour period and analyzed for the parent drug and one of its metabolites, deacetyldiltiazem (DAD). Concurrent cimetidine produced a significant (p less than 0.05) increase in diltiazem levels at most time points, in peak concentration and area under the concentration-time curve. These variables were also increased during concurrent ranitidine administration but did not reach statistical significance. The DAD plasma concentration was below measurable levels during the control phase but increased during concurrent cimetidine and ranitidine administration. Caution should be exercised when diltiazem is administered concurrently with cimetidine and possibly, ranitidine.     

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.     

Effect of domperidone on cimetidine and ranitidine absorption in rabbits

Cimetidine and ranitidine absorption were studied after oral administration to rabbits, alone or in combination with oral and intravenous domperidone. 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 cimetidine and ranitidine administration. Assays of cimetidine and ranitidine in plasma samples were carried out using HPLC method. Domperidone overall significantly reduced the area under the plasma concentration-time curve (AUC) by approximately 30 per cent for both drugs. However, domperidone had little effect on the maximum plasma concentration (Cmax), the time taken to reach the maximum plasma concentration (Tmax), and the elimination half-life (t1/2) of cimetidine and ranitidine. The results suggest that domperidone affects the extent but not the rate of cimetidine and ranitidine absorption by enhancing gastric emptying.     

Absolute bioavailability and effect of food and antacid on diazepam absorption from a slow-release preparation

A series of healthy volunteers received a single 7.5-mg intravenous dose of diazepam on one occasion and a single 15-mg oral dose of slow-release diazepam (DZ-SR) on another occasion. Diazepam concentrations were measured by gas chromatography in multiple plasma samples drawn during seven days after each dose. Absorption of diazepam from DZ-SR was slow, with mean +/- S.E. peak concentrations attained at 3.8 +/- 0.5 hours after dosage. Absolute bioavailability of DZ-SR averaged 0.98 +/- 0.06. In two other studies, diazepam absorption from DZ-SR was evaluated when coadministered with a standard breakfast or with an antacid preparation (Maalox). Neither food nor antacid altered the rate of diazepam absorption and did not impair the completeness of absorption. Higher peak total plasma diazepam concentrations occurred in the postprandial as opposed to the fasting state, but this was an artifact of reduced protein binding (increased free fraction) due to fasting. Thus, diazepam absorption from DZ-SR is slow and essentially complete.     

The effects of an antacid or cimetidine on the serum concentrations of azithromycin.

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0-48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.     

The paradoxical effect of cimetidine and ranitidine on glibenclamide pharmacokinetics and pharmacodynamics.

The potential interactions between H2-receptor antagonists, cimetidine and ranitidine, and glibenclamide were studied in 15 non-smoking male volunteers. The study consisted of six treatment phases. Treatment A (3 h oral glucose tolerance test) consisted of 75 g dextrose in 300 ml carbonated water. Treatment B consisted of one 5 mg tablet of glibenclamide in addition to a glucose tolerance test. Treatment C, cimetidine 300 mg orally four times daily for 4 days and Treatment D, ranitidine 150 mg orally twice daily for 4 days were administered in a randomized, crossover fashion. On day 3 of Treatments C and D, subjects received an oral glucose tolerance test. On day 4 of Treatments C and D, subjects received 5 mg of glibenclamide in addition to cimetidine (Treatment E) or ranitidine (Treatment F) and an oral glucose tolerance test. Compared with the control treatment, cimetidine increased the glibenclamide AUC (973 vs 710 ng ml-1 h), but during ranitidine dosing glibenclamide AUC (726 ng ml-1 h) was not significantly different from the control. Apparent oral glibenclamide clearance decreased from 8.25 l h-1 under the control treatment to 6.0 l h-1 following cimetidine but was unchanged during ranitidine (7.97 l h-1). Plasma glucose concentrations were unexpectedly higher when glibenclamide was administered with cimetidine or ranitidine (glucose AUC 237 mg dl-1 h, 228 mg dl-1 h) when compared with glibenclamide administered alone (195 mg dl-1 h, P less than 0.0001). Plasma insulin concentrations were significantly elevated when H2-receptor antagonists and glibenclamide were administered concurrently.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of food and antacid on absorption of orally administered ticlopidine hydrochloride

Ticlopidine is a potent inhibitor of platelet aggregation. Absorption of ticlopidine after oral dosing is rapid and complete. Ticlopidine is extensively metabolized with a relative minor component of unchanged ticlopidine in plasma. The randomized crossover study described here was undertaken to examine the effect of food and antacid on the oral bioavailability of a single dose of ticlopidine (250 mg) in normal volunteers. After postprandial treatment the rate and extent of absorption of ticlopidine was earlier and greater relative to fasting treatment [tmax = 1.71 +/- 0.33 hr (fed) vs 1.92 +/- 0.56 hr (fasting) and AUC0-infinity = 2.164 +/- 0.813 micrograms X hr/mL (fed) vs 1.808 +/- 1.052 micrograms X hr/mL (fasting)]. The oral bioavailability of ticlopidine was increased by 20% when taken after a meal. In contrast, absorption of ticlopidine administered after antacid treatment was approximately 20% lower than under fasting conditions. Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance.     

Effect of food and an antacid on quinidine bioavailability

Two 200 mg quinidine sulfate tablets were administered to nine healthy male subjects in the fasting state, immediately after a balanced meal, and with 30ml of aluminum hydroxide gel using a complete crossover design. Serum and urine samples were taken over 32 and 60 h respectively. Quinidine concentrations were measured using a high-performance liquid chromatography assay specific for quinidine. Computer fitting of the data to several models indicated that a one-compartment model with zero-order absorption and a lag time best fit all the data. Quinidine elimination and urine pH were unaffected by the study conditions. While the maximum serum concentration (C_max) and area under the serum concentration—time curve (AUC) were unaffected by administration of quinidine with food or antacid, there was a 44 per cent increase (p < 0·10) in time to C_max (t_max) following quinidine administration with food. Thus, while the extent of quinidine absorption was unaffected by food or the antacid used, the rate of quinidine absorption was significantly reduced by food as reported earlier.     

Ulcer-protective effect of cimetidine and an antacid. Animal experiment study on an ulcer model with protracted histamine liberation

The ulcer-protective effect of cimetidine has been compared with that of an antacid (Solugastril) containing aluminium hydroxide and calcium carbonate. Ulcers have been produced by using dialysis sacks containing histamine. This model corresponds to stress ulcers observed in risk patients. Both cimetidine and the antacid were capable of inhibiting the ulcer development in corresponding doses and applications: The present results show that an antacid might be qualified for the treatment of stress ulcers in the human therapy.     

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.     

The effect of an antacid on the bioavailability of indomethacin

Summary The biovailability of indomethacin from two indomethacin-antacid (aluminum hydroxide magnesium carbonate and magnesium hydroxide) combinations was compared with the bioavailability of oral indomethacin. Relative bioavailability was estimated by three methods: comparison of plasma concentrations at various times, comparison of areas under plasma concentration time curves, and comparison of the amount of drug excreted unchanged in the urine. A double blind three-way crossover study was conducted in twelve healthy volunteers. The combination with the slightly smaller amount of antacid (preparation A) showed significantly decreased bioavailability by all three methods in comparison with indomethacin alone (preparation C). The combination with the larger amount of antacid (preparation B) was also less bioavailable than preparation C. This effect was significant only for the comparison of areas under curves and not for plasma levels, although the mean plasma levels produced by preparation B at all times were lower than those for preparation C. These findings suggest that aluminum hydroxide magnesium carbonate and magnesium hydroxide decrease the bioavailability of indomethacin.A preliminary report has been published as an abstract in Clin. Res.23, 219, 1975     

The influence of cimetidine versus ranitidine on doxepin pharmacokinetics

Summary The effect of cimetidine and ranitidine on doxepin pharmacokinetics was studied in 6 healthy volunteers. Each subject completed 3 study phases: Treatment A, 9 consecutive doses of 50 mg doxepin (once daily); Treatment B, same as Treatment A but co-administration of cimetidine 600 mg b.i.d. starting after the sixth doxepin dose and continuing until approximately 2 days following discontinuation of doxepin administration; Treatment C, identical to Treatment B but with ranitidine 150 mg b.i.d. instead of cimetidine. Unlike ranitidine, cimetidine co-administration resulted in a significant increase in steady state plasma levels of doxepin (4.7, 9.0 and 4.5 ng/ml during Treatments A, B and C respectively) but not desmethyldoxepin (4.1, 4.6 and 4.2 ng/ml during Treatments A, B and C respectively). Elimination half-lives of doxepin and desmethyldoxepin were prolonged by cimetidine co-administration (19.6 and 26.2 h respectively), but remained unchanged during the ranitidine treatment phase (13.3 and 18.4 h) as compared to the control phase i.e. Treatment A (13.2 and 19.0 h). These results show that cimetidine, unlike ranitidine, significantly inhibits the biotransformation of doxepin. This data has clinical implications when the co-administration of tricylic antidepressants and H₂-receptor antagonists are indicated.     

The effects of cimetidine and ranitidine on the pharmacokinetics of cifenline.

Twelve healthy subjects completed an open single dose study to evaluate the effect of co-administration of cimetidine and ranitidine on the pharmacokinetics of cifenline. Each subject received a single 160 mg dose of cifenline alone, in combination with cimetidine (300 mg four times daily), and with ranitidine (150 mg twice daily). The H2-receptor antagonists were given with breakfast 1 h prior to cifenline dosing and continuing for 48 h. Co-administration of cimetidine significantly increased Cmax (27%) and AUC (44%) and prolonged the half-life (30%) of cifenline. There were no differences in these parameters when ranitidine was co-administered with cifenline. The results of this study suggest that cimetidine, but not ranitidine, lowers the clearance of cifenline by inhibition of hepatic oxidative metabolism.