Ranitidine bioavailability and disposition kinetics in patients undergoing chronic hemodialysis.

The absorption and disposition of single-dose intravenous (i.v.) and oral ranitidine were evaluated in 6 patients undergoing chronic hemodialysis. Ranitidine was given as either 50 mg (0.16 mM) i.v. or 150 mg (0.48 mM) tablets 4 h prior to hemodialysis according to a randomized cross-over design with tests separated by 2 weeks. Following i.v. administration, the peak serum ranitidine concentration was 761 +/- 207 micrograms/l (mean +/- SD) and the observed peak after the oral dose was 833 +/- 206 micrograms/l at 3.5 +/- 1.2 h. To convert micrograms/l to microM/l, divide by 314. The terminal elimination rate constants for the i.v. and oral doses were 0.062 +/- 0.013 and 0.058 +/- 0.004 h-1, respectively, with an apparent volume of distribution of 139.6 +/- 35.3 liters and total body clearance 8.5 +/- 1.6 liters/h for the i.v. dose. Hemodialysis clearances during the i.v. and oral studies were 3.2 +/- 0.9 and 3.1 +/- 1.0 liters/h, respectively, and the mean amount removed by hemodialysis following i.v. administration was 3.9 +/- 2.7 mg. The bioavailability of ranitidine was 54.3 +/- 13.5%. Based on these single-dose data, a daily oral dose of 150 mg ranitidine in patients with end-stage renal disease should provide a mean ranitidine serum concentration of approximately 350 micrograms/l with less than 10% of body stores of ranitidine being lost during any dialysis session.

Ranitidine pharmacokinetics in continuous ambulatory peritoneal dialysis.

Ranitidine kinetics in renal failure were evaluated in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD). On separate occasions each patient received either 50 mg intravenously (i.v.) or 150 mg orally of ranitidine HCl. Following i.v. administration, the plasma concentration vs time curve was best described by a two compartment model with firstorder elimination. The mean +/- SD distribution and elimination rate constants were 2.47 +/- 0.78 and 0.098 +/- 0.013 h, respectively. The area under the serum concentration vs time curve after the i.v. dose was 5979 +/- 2870 micrograms X h X l-1, resulting in a mean volume of distribution of 76.8 l and a total body clearance of 126 ml X min-1. Following oral administration the observed maximum plasma concentration was 904 +/- 483 micrograms X l-1 at 4.2 +/- 1.8 h, and the bioavailability was 69.7 +/- 35.6%. The peritoneal clearance of ranitidine was 3.2 +/- 0.7 and 2.6 +/- 0.6 ml X min-1 for the i.v. and oral groups, respectively. The amount of drug removed by dialysis was 561.2 +/- 336.2 micrograms for the i.v. and 1197.1 +/- 602.3 micrograms for the oral group. Four patients in the i.v. group had urine output during the study period with renal ranitidine clearance values of 9.9 +/- 9.9 ml X min-1. Two patients in the oral group had urine output and corresponding renal ranitidine clearance values of 5.1 and 20.1 ml X min-1. A dosage regimen for ranitidine is proposed based on ranitidine kinetics in patients undergoing CAPD.

A multicenter study of ranitidine treatment of duodenal ulcers in the United States.

Treatment of duodenal ulcer with the histamine H2-receptor antagonist, ranitidine, was assessed in a double-blind, randomized, multicenter trial in which patients were treated for two consecutive 4-week periods with ranitidine 150 mg b.i.d. or a placebo. All patients were allowed to take antacids as necessary for symptoms. Three hundred eighty-two patients were entered and 355 completed the first 4-week trial period. Ranitidine significantly improved healing at 2 weeks (37 versus 19%, p less than 0.01) and at 4 weeks (73 versus 45%, p less than 0.01), with better relief of pain and lower use of antacids. In the second 4-week trial period, 124 unhealed patients from the first 4 weeks were re-randomized. Ranitidine treatment resulted in a greater healing rate regardless of previous treatment (p less than 0.05). In this trial, side effects were uncommon and not different between placebo and the tested drug. One case of hepatitis in the ranitidine treated group was presumed on the evidence to be non-A non-B. Ranitidine is effective and appears to be safe in the treatment of duodenal ulcer and its symptoms.

Pharmacokinetics of ranitidine in patients with renal failure.

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.

Pharmacokinetics of ranitidine following oral administration with ascending doses and with multiple-fixed doses.

The aim of these studies was to further delineate pharmacokinetic characteristics of ranitidine, a new histamine H2-receptor antagonist. In one study, ranitidine was administered orally to six normal men in increasing doses of 100 mg, 150 mg, 250 mg, and 400 mg weekly over a four-week period. The peak serum concentrations increased with the corresponding increases in dose but the time needed to reach peak serum concentration did not vary significantly with increased doses. The pharmacokinetic parameters were calculated for each subject at each of the four dose levels. The total area under the curve (AUC) at the four different doses was linearly related to the dose for each individual subject; and a plot of AUC versus dose had a correlation coefficient of .886 (P less than .001). The apparent plasma clearance did not vary with the increase in dose; and the average corrected clearance values ranged between 6.7 and 10 mL/(min X kg). Elimination half-life was between 2.6 and 3.0 hours; and the volume of distribution (Vd area) was between 1.6 and 2.4 L/kg. About 35% of the ranitidine dose was excreted in the urine in the unchanged form over a 12-hour excretion interval. In the second study, ranitidine was administered orally to 12 normal subjects in doses of 150 mg and 200 mg twice daily for 28 days. The pharmacokinetic parameters for ranitidine with multiple-dose treatment were similar to those obtained with single-dose administration. Predose ranitidine concentrations (trough levels) did not increase with multiple dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease.

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.

The effects of several weeks of ethanol consumption on ethanol kinetics in normal men and women.

We examined in normal men and women the effects of chronic ethanol consumption and the coadministration of cimetidine and ranitidine on the kinetics of ethanol. We found that the consumption of 45 gm ethanol per day for 3 weeks increased the apparent volume of distribution of ethanol in men from 732 to 884 ml/kg (P less than 0.01) but had no such effect in women (697 ml/kg before ethanol and 746 ml/kg after chronic ethanol consumption). This combined therapy had no effect on the rate of ethanol disappearance in either sex. In men the rate of disappearance was 165 mg/L/hr before and 168 mg/L/hr after chronic consumption, while in women the respective values were 209 and 203 mg/L/hr. The addition of either cimetidine or ranitidine had no effect on either parameter compared with values observed on day 22 of the study. In view of the known inhibitory effects of cimetidine on cytochrome P-450-dependent enzymes, our data suggest that this enzyme system does not metabolize a significant fraction of ingested ethanol in subjects who have consumed moderate doses of alcohol for several weeks.

Effects of cimetidine and ranitidine on the conversion of prednisone to prednisolone.

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.

Protocol design for recent duodenal ulcer maintenance trials.

The long-term efficacy and safety of ranitidine for the prevention of duodenal ulcer recurrence were studied in two sets of double-blind, randomized, multicenter clinical trials. Ranitidine 150 mg at bedtime was compared with either cimetidine 400 mg at bedtime or placebo in the United States and Europe. To meet one of the objectives of the studies (that is, to provide a mechanism for standardizing sponsored clinical research methodology on an international basis), several features were incorporated into the study protocol. These features included identical case report forms for all trials, central clinical laboratories in the United States and Europe, monitoring of all sites to ensure that the United States style was followed, and the all sites to ensure that the United States style was followed, and the completion in the United States of all data processing and analysis. Additionally, to overcome flaws in the design of earlier trials with similar drugs, patients were examined endoscopically at more frequent intervals to detect an ulcer recurrence without symptoms, and the data were analyzed for recurrence rates by the life-table method. This method more accurately reflects the true ulcer recurrence rate than the crude-rate method that was used in earlier trials.

The influence of H2-receptor antagonists on steady-state concentrations of propranolol and 4-hydroxypropranolol.

Twelve healthy male volunteers were treated with 1200 mg/day cimetidine, 300 mg/day ranitidine, or no H2-receptor antagonist (control) for seven days in a sequence determined by Latin-square design. Each treatment period was separated by a seven-day washout. On the third day of each treatment period, 80 mg propranolol every 12 hours for nine doses was initiated. Whole blood concentrations of propranolol and 4-hydroxypropranolol were measured at 12 time points during the 12-hour period following administration of the last propranolol dose. Heart rate was measured before each blood sample was withdrawn. Cimetidine treatment was associated with a 47 per cent increase in the area under the propranolol concentration-time curve and a 17 per cent increase in elimination half-life of propranolol. Ranitidine had no significant effect on the concentration-time profile of propranolol. There were no significant differences in the 4-hydroxypropranolol pharmacokinetic parameters during any of the treatments. There was, however, a significant decrease in the average 4-hydroxypropranolol-to-propranolol steady-state concentration ratio during the cimetidine treatment. There was no significant difference in heart rate between any of the treatments. The elevation of propranolol concentrations during cimetidine treatment is likely due to metabolic inhibition by cimetidine.

Ranitidine disposition and systemic availability in hepatic cirrhosis.

Single-dose ranitidine kinetics were studied in 10 patients with cirrhosis as proved by liver biopsy. All were clinically stable. After an overnight fast, ranitidine was given in a randomized crossover order as a bolus intravenous injection (50 mg) or was taken by mouth (150 mg). Terminal t1/2 was 2.7 +/- 0.4 hr after oral dosing and 2.9 +/- 0.4 hr after intravenous injection. Total plasma clearance was 470 +/- 170 ml/min and the steady-state volume of distribution was 1.2 +/- 0.2 l/kg. There was considerable intersubject variability in the ranitidine serum concentration-time profile after oral dosing. Systemic availability as assessed by AUC analysis was 58% +/- 11%. Not all of the dose could be recovered in the urine as unchanged ranitidine and its known metabolites after intravenous injection. At 0.5 microgram/ml the serum protein binding of ranitidine was 4.6% +/- 1.3%. It is concluded that disposition of ranitidine in these 10 stable subjects with cirrhosis was not significantly altered. The minor changes observed in some were as likely to be the result of secondary perturbations in physiologic status as to effects of cirrhosis on drug metabolism.

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.

Inhibition of theophylline clearance by cimetidine but not ranitidine.

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on theophylline pharmacokinetics and to determine whether the previously described cimetidine-theophylline interaction is dose dependent. Twelve healthy adult men were given a 6-mg/kg intravenous aminophylline dose on four occasions. Subjects were randomly assigned four treatments: no treatment (control); cimetidine, 1,200 mg/day; cimetidine, 2,400 mg/day; and ranitidine, 300 mg/day. Cimetidine, 1,200 mg/day, significantly decreased theophylline clearance by 36% (range, 22% to 49%) and increased the mean elimination half-life from 5.7 hours (control) to 9.2 hours. A significant difference was not found between the two cimetidine dosages, indicating dose independence of the interaction over the dosage range studied. Ranitidine did not significantly alter theophylline pharmacokinetics. Theophylline plasma protein binding was not affected by any treatment. The relative effects of cimetidine and ranitidine on the elimination of cytochrome P-450 metabolized drugs such as theophylline indicate a useful property of ranitidine as compared with cimetidine.

Ranitidine does not impair oxidative or conjugative metabolism: noninteraction with antipyrine, diazepam, and lorazepam.

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.

Effects of ranitidine and of cimetidine on pentagastrin-stimulated gastric acid secretion.

We compared the effect of oral and intravenous ranitidine, a new H2-receptor antagonist, with that of cimetidine on pentagastrin-stimulated gastric acid secretion in normal subjects. Ranitidine in intravenous doses of 20, 60, and 100 mg and oral doses of 100, 150, and 200 mg inhibited acid secretion. Only the 100 mg iv ranitidine dose was substantially more effective than cimetidine. Comparable dose-related decreases in gastric secretory volume were observed. Acid inhibition correlated strongly (r = 0.90) with plasma ranitidine concentration, with the estimated plasma concentration producing 50% inhibition (IC50) being 95 ng/ml. Maximal acid inhibition achieved was 87.3%. We conclude that ranitidine is a potent inhibitor of gastric acid secretion and should be a valuable addition to the medical treatment of acid-peptic disease.

Ranitidine bioavailability and kinetics in normal male subjects.

Ranitidine is a potent histamine H2-receptor blocker that inhibits histamine- and pentagastrin-induced gastric acid secretion. After doses of 100 mg both intravenously and orally ranitidine kinetics and bioavailability were investigated in a single dose two-way crossover study in 12 normal men. Serum concentrations of ranitidine were determined by radioimmunoassay and urine concentrations by an ion-pair HPLC method. Intravenous data were fitted to exponential equations with the computer program NONLIN; model-independent kinetic parameters were calculated. Elimination t 1/2, plasma clearance, renal clearance, hepatic clearance, and volume of distribution for ranitidine after intravenous injection were 2 hr, 10.4 ml/(min X kg), 7.2 ml/(min X kg), 3.1 ml/(min X kg), and 1.82 l/kg, respectively; after oral doses mean t 1/2 was 2.7 hr and mean bioavailability was 52%. The average cumulative urinary excretion of ranitidine as percent of dose was 69.4 +/- 6.1% and 26.7 +/- 7.2% after intravenous and oral doses.

Clinical comparison of cimetidine and ranitidine.

Ranitidine is a histamine H2-receptor antagonist that differs structurally from cimetidine. We assessed its kinetics, potency, and duration of effect in patients with chronic duodenal ulcers. Ranitidine had an absorption lag time of approximately 30 min, an absorption half-life (t 1/2) of approximately 40 min, and an elimination t 1/2 of 3 hr, all differing from those of cimetidine. It is five times as potent, so that equal doses of ranitidine induce considerably longer suppression of both basal and food-stimulated gastric acid secretion than cimetidine.

Trimethobenzamide HCl in the treatment of nausea and vomiting associated with antineoplastic chemotherapy.

Fifty-five patients undergoing chemotherapy for various neoplastic processes were treated with trimethobenzamide or placebo to control nausea and vomiting. Trimethobenzamide was shown to be significantly better than placebo in relieving periodic and total nausea over the 48-hour study. Vomiting incidence was also reduced in the group receiving trimethobenzamide. Differences were noted in the degree of emetic stimulus associated with different chemotherapeutic regimens. No side effects attributable to trimethobenzamide were recorded.

Pharmacokinetics of amoxicillin and ampicillin: crossover study of the effect of food.

The effect of food on the absorption of amoxicillin and ampicillin was studied in 16 normal subjects in a double-blind crossover study after each subject was given a single oral 500-mg dose. Serum drug levels were analyzed, assuming a one-compartment linear model with first-order absorption and absorption delay, area under the curve, and urinary recovery. Variations in kinetic parameters were examined by using analysis of variance. The results showed little or no effect of fasting versus nonfasting on amoxicillin absorption, as evidenced by peak serum levels (8.9 mug/ml, fasting, 8.8 mug/ml, nonfasting), area under the curve (26.9 mug/ml per 70 kg, fasting, 22.2 mug/ml per 70 kg, nonfasting), and urinary recovery (47%, fasting; 44%, nonfasting). Ampicillin absorption was significantly decreased in the nonfasted group by the same parameters (peak level: 5.4 mug/ml, fasting, 4.0 mug/ml, nonfasting; area under the curve, 17.4 h.mug/ml, fasting, 12.0 h.mug/ml, nonfasting; urinary recovery, 37%, fasting, 29%, nonfasting). These results confirm the reliable absorption of orally administered amoxicillin in the fed as well as the fasted state.