The effect of cimetidine dose timing on oral propranolol kinetics in adults

Ten healthy male volunteers completed a study to determine the effect of cimetidine dose timing on the oral clearance of propranolol. Propranolol HCl 160 mg as tablets, was administered daily at 8 AM for 4 consecutive days on three occasions. In addition, cimetidine HCl 800 mg as tablets, was administered either simultaneously in the morning with propranolol (8 AM), at bedtime (10 PM), or not at all (control). Each treatment was separated by at least a 3-day washout. Propranolol and cimetidine serum samples were measured over the 24-hour dosing interval after the last propranolol dose. Cimetidine administration at 8 AM and 10 PM was associated with significant mean increases in the propranolol area under the serum concentration-time curve of 26% and 41%, respectively (P less than .002). The mean elimination half-life of propranolol was 6.3 hours during all three treatments. There was no significant difference in area under cimetidine serum concentration time curve between 8 AM and 10 PM dosing. Dosing cimetidine at bedtime 10 hours before propranolol does not diminish the magnitude of interaction.     

The influence of diltiazem versus cimetidine on propranolol metabolism.

The present study was undertaken to examine whether the inhibitory effect of diltiazem on the metabolism of propranolol differs from that of cimetidine. Six healthy male volunteers received a single oral dose of 20 mg propranolol with pretreatment with placebo, 60 mg diltiazem, or 400 mg cimetidine three times daily for 4 days. Diltiazem and cimetidine increased the area under the concentration (AUC) of propranolol and its glucuronide. Cimetidine also increased the urinary excretion of propranolol glucuronide. There were no significant differences in the AUC of 4-hydroxypropranolol (4OHPPL) and its conjugates or the urinary excretion of conjugated 4OHPPL. Diltiazem increased the AUC of naphthoxylactic acid (NLA) and the urinary excretion to NLA. After cimetidine pretreatment, there was the trend toward a decrease in the partial metabolic clearance to 4OHPPL and a significant decrease in that of NLA. These results suggest that diltiazem and cimetidine inhibit the oxidation pathways of propranolol in different manners. Cimetidine might inhibit both oxidative pathways to 4OHPPL and NLA, whereas diltiazem might not inhibit the pathway to NLA.     

Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC0-infinity values (573.5 vs. 146.4 ng.hr/ml, p = 0.0001) and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropranolol indicates that etintidine also increased the AUC0-24 values (43.8 vs. 16.4 ng.hr/ml, p = 0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

The effect of age on diurnal variation in the pharmacokinetics of propranolol in hypertensive subjects

Summary There is diurnal variation in the absorption rate of propranolol in younger subjects. This study was undertaken to examine the effect of age on the chronopharmacokinetics of propranolol.We gave 20 mg of propranolol orally to 13 younger and 11 older hypertensive subjects at 09.00 h (day study) or 21.00 h (night study) in a cross-over design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 h after dosage. In the younger subjects the absorption rate constant (k_a) of propranolol and its maximum plasma concentration (C_max) were significantly higher and the time to maximum concentration (t_max) was significantly shorter in the day than at night. There were similar time-variant changes in C_max and t_max for 4-hydroxypropranolol and naphthoxylactic acid. In contrast, there were no time-variant changes in k_a, C_max and t_max of propranolol and its metabolites in the older subjects.These results suggest that propranolol is absorbed more rapidly after morning dosing than after night-time dosing in younger but not in older subjects. Based on these findings, we speculate that the time-variance in the absorption rate or first-pass elimination, or both, of propranolol diminish with age.     

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.     

Steady state relative bioavailability and pharmacokinetics of oral propranolol in black and white North Americans

The steady state bioavailability and pharmacokinetics of propranolol over two consecutive dosing intervals were investigated in 18 black and 10 white normal volunteers following the administration of 20 mg of a test and reference oral dosage form, respectively, every 6 h. There were no differences (p greater than 0.05) between dosage forms in the mean (n = 28) area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) or time to Cmax (tmax) for propranolol or its active metabolite, 4-hydroxypropranolol. However, as a group blacks had lower plasma concentrations of propranolol during the second dosing interval (AUC-2 and Cmax-2, respectively) were significantly (p less than 0.05) lower in blacks, but there were no ethnic differences (p greater than 0.05) in tmax. The mean AUC and Cmax for the 4-hydroxylated metabolite during both dosing intervals were significantly (p less than 0.05) lower in blacks. Mean oral clearances of propranolol, assuming complete absorption, (range: 42.1-54.5 ml min-1 kg-1) were similar (p greater than 0.05) in each racial group. There were no substantial changes in heart rate or blood pressure in blacks or whites following propranolol administration. These data suggest that for oral propranolol, blacks have different absorption and disposition characteristics than whites.     

Plasma concentrations of propranolol and 4-hydroxypropranolol during chronic oral propranolol therapy.

1 The plasma levels of propranolol and 4-hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4-hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean (+/- s.d.) plasma concentration ratio of 4-hydroxypropranolol to propranolol was 0.130 (+/- 0.005); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4-hydroxypropranolol and that of propranolol. 5 Propranolol and 4-hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.     

Mechanism for the interaction between triazolam and cimetidine

Four normal volunteers each received three intraduodenal infusions of 0.5 mg triazolam solutions. Three treatments were: a pH 2.3 solution in which 47 per cent of the dose had hydrolysed to form a triazolo-benzophenone (TB); a pH 6.0 solution containing negligible TB; the pH 6.0 solution administered during cimetidine treatment (1200 mg day-1). TB was stable in serum and only very low TB serum concentrations were observed from the pH 2.3 treatment. No difference was observed in any triazolam pharmacokinetic parameter between the pH 6.0 and the pH 2.3 treatments. Cimetidine increased the triazolam AUC infinity and Cmax by 54 and 35 per cent, respectively. These results indicate that TB undergoes extensive presystemic conversion to triazolam and the triazolam-cimetidine interaction occurs primarily through a reduction in triazolam clearance.     

Do beta blockers differ in their effects on hepatic microsomal enzymes and liver blood flow?

The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.     

Lack of interaction between nefazodone and cimetidine: a steady state pharmacokinetic study in humans.

The steady-state pharmacokinetic interaction between nefazodone and cimetidine was evaluated in a three-period crossover study consisting of three treatments of 1 week duration with a 1 week washout between treatments. The 18 healthy, male study subjects received: nefazodone hydrochloride 200 mg twice daily (every 12 h) for 6 days; cimetidine 300 mg four times daily for 6 days; and 200 mg nefazodone hydrochloride twice daily + 300 mg cimetidine four times daily for 6 days. On day 7 of each treatment, only the morning dose was administered. Serial blood samples were collected for pharmacokinetic analysis after drug administration on day 7 of each treatment; blood samples for trough levels (Cmin) to assess attainment of steady state, were also collected just prior to the morning doses on days 2-7 of each study period. Plasma samples were assayed for cimetidine, and nefazodone and its metabolites hydroxynefazodone and m-chlorophenylpiperazine by specific, validated h.p.l.c. methods. Statistical analyses of Cmin data indicated that, regardless of treatment, steady state was achieved for cimetidine by day 2 and for nefazodone and its metabolites by day 3 of multiple dosing, and that there were no significant differences in Cmin levels between treatments. When nefazodone and cimetidine were co-administered for 1 week, no change in steady-state pharmacokinetic parameters for cimetidine, nefazodone or hydroxynefazodone was observed compared with each drug dosed alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sucralfate on the bioavailability of cimetidine

Summary Twelve, healthy fasting, subjects received 200 mg cimetidine orally either with water or 1 g sucralfate in a randomized, single dose, two-way crossover study. Blood samples were taken for 12 h and urine was collected for 24 h. Cimetidine in plasma and urine was analysed by HPLC. There was no significant difference between the two treatments in peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve and urinary excretion. The results indicate that sucralfate did not reduce the bioavailability of cimetidine.     

Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H₂ -blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal® (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC_0–,values (573.5 vs. 146.4 ng·hr/ml, p=0.0001)and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropanolol indicates that etintidine also increased the AUC_0–24 values (43.8 vs. 16.4 ng·hr/ml, p=0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine--studies in patients with peptic ulcer disease.

1 The absorption of a single oral dose of cimetidine taken on a fasting stomach or together with a meal was studied in 28 patients before and during 12 weeks treatment with cimetidine. 2 No significant changes in bioavailability were seen during treatment measured as the area under the blood concentration curve (AUC). 3 AUC after a single dose of 400 mg cimetidine was 2.05 times the area after a 200 mg dose. 4 There was a good correlation between AUC and the dose of cimetidine given corrected for body weight (r=0.89). 5 There was no difference in bioavailability if 200 mg cimetidine was taken on a fasting stomach or together with a beef steak meal. 6. During fasting conditions there was a peak in blood concentration at about one hour followed by a second unexplained peak during the third to fifth hour after dose administration. 7 With food the initial rise in blood concentrations was slower and there was only one peak occurring about 2 h after dose administration.     

Effect of duration of lidocaine infusion and route of cimetidine administration on lidocaine pharmacokinetics

The effects of the duration of lidocaine infusion and the route of cimetidine administration on lidocaine pharmacokinetics were evaluated in a randomized, three-phase crossover study of six healthy men. Lidocaine hydrochloride 100 mg was administered intravenously over two minutes, and plasma lidocaine concentrations were determined before treatment and at various intervals for three hours. Immediately after the three-hour sample was obtained, a second 100-mg dose of lidocaine hydrochloride was given, followed by a 21-hour constant infusion at a rate of 2 mg/min. Plasma lidocaine concentrations were determined at various intervals during the infusion and for eight hours afterward. Urine was collected during the last five hours of the infusion and assayed for lidocaine, monoethylglycinexylidide (MEGX), and glycinexylidide (GX). The following treatments were administered to each subject in a crossover manner: a placebo tablet every six hours, beginning two days before lidocaine administration; cimetidine 300 mg orally every six hours, beginning two days before lidocaine administration; and cimetidine hydrochloride 300 mg i.v. every six hours, beginning one hour before lidocaine administration. Each medication was given until the lidocaine infusion was discontinued. Subjects fasted and remained supine throughout each treatment period. Oral cimetidine increased the area under the concentration-time curve for lidocaine by 14.7% and increased the elimination half-life of lidocaine; i.v. cimetidine did not have a significant effect on lidocaine disposition. Lidocaine clearance was 34% lower under steady-state than single-dose conditions, but the effects of cimetidine on lidocaine disposition were similar under both conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cimetidine increases steady state plasma levels of propranolol.

1 The influence of cimetidine (1000 mg daily) on propranolol steady state plasma levels has been studied in seven normal volunteers. Cimetidine was used as a 200 mg normal release tablet whereas propranolol was given as a 160 mg slow release formulation once daily. 2 After 1 day of cimetidine treatment (day 9 of the study) the mean (Css) and minimal (Css min) propranolol steady state plasma levels increased significantly from 24.1 +/- 14.9 ng/ml (mean +/- s.d.) to 39.2 +/- 27.7 ng/ml (P = 0.01) and from 14.8 +/- 9.3 ng/ml to 27.1 +/- 21.2 ng/ml (P = 0.03), respectively. The apparent oral clearance (Clo) was reduced from 6.7 +/- 4.3 l/min to 4.6 +/- 3.11/min (P = 0.006). 3 A prolongation of cimetidine administration to 5 days (day 13 of the study) intensified this effect significantly (P = 0.02): Css of propranolol was elevated from 23.2 +/- 14.4 ng/ml to 44.9 +/- 26.7 ng/ml (P = 0.003); Css min was increased from 14.1 +/- 10.2 ng/ml to 28.4 +/- 17.9 ng/ml (P = 0.02) while Clo decreased from 6.9 +/- 4.1 1/min to 3.3 +/- 1.61/min (P = 0.006). 4 We conclude that the drug interaction between propranolol and cimetidine leads to significant elevations of propranolol steady state plasma concentrations which may cause a clinically relevant enhancement of the effect of a given dosage. This requires careful observation of patients under concomitant treatment with propranolol and cimetidine.     

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

AIMS: To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. METHODS: Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. RESULTS: Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. CONCLUSIONS: Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.     

Betaxolol and glucose-insulin relationships: studies in normal subjects taking glibenclamide or metformin.

1. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single-blind crossover group study. 2. After a 4 day run-in period on no treatment, six subjects took glibenclamide 2.5 mg twice daily, and six subjects took metformin 850 mg twice daily from day 5 to day 19. All subjects took betaxolol 20 mg daily from day 10 to day 13, and placebo from day 5 to day 10 and from day 13 to day 19. 3. Plasma glucose and insulin concentrations were measured fasting and 60 min after a standard breakfast for 3 successive days during each study treatment; plasma potassium, sodium and betaxolol concentrations were also measured. 4. Fasting glucose, insulin and potassium concentrations did not differ significantly between betaxolol and placebo treatment periods in either glibenclamide- or metformin-treated groups. Post-prandial glucose and insulin concentrations were lower and higher, respectively, relative to fasting concentrations but there was no significant difference between any of the treatment periods. Glibenclamide produced significant increases in insulin concentrations compared with drug-free periods (P less than 0.01). Plasma potassium and sodium concentrations were not affected by any of the treatments. 5. Plasma betaxolol concentrations were adequate for beta 1-adrenoceptor blockade. 6. This study suggests that selective beta 1-adrenoceptor blockade with betaxolol does not change fasting or post-prandial glucose-insulin relationships during simultaneous treatment with either the sulphonylurea glibenclamide or the biguanide metformin.     

Lack of interaction between cimetidine and buspirone

Simultaneous administration of cimetidine and many benzodiazepine anxiolytics has resulted in decreased body clearance and marked prolongation of the half-life of these agents. The pharmacokinetic interaction of buspirone, a new nonbenzodiazepine anxiolytic, and cimetidine was studied in 10 healthy male volunteers. Each received, in order, buspirone 45 mg/day (days 1-7), no drug (days 8-14), cimetidine 1 g/day (days 15-21), buspirone 45 mg/day plus cimetidine 1 g/day (days 22-28), and cimetidine 1 g/day (days 29-31). Buspirone and 1-pyrimidinyl piperazine (1-PP), an active metabolite, pharmacokinetics, urinary excretion of cimetidine, a manual dexterity test, the Stroop color-word interference test, and a visual analog mood scale were evaluated on each treatment. There were no significant (p greater than 0.05) differences among treatments for any measurement except for a slight (31%) but significant (p less than 0.05) increase in the 1-PP Cmax value. These results suggest that within the normal therapeutic dosage ranges for both drugs, it is unlikely that a clinically significant interaction between them will occur.     

Pharmacokinetic and pharmacodynamic comparison of two doses of long acting propranolol (80 and 160 mg) in healthy subjects.

1. The kinetics and dynamics of long acting propranolol 80 mg and 160 mg were examined after single oral doses to 12 healthy volunteers. 2. Long acting propranolol 160 mg produced a twofold increase in mean peak blood propranolol concentration and AUC compared with the lower dose. There was no difference in elimination half-life, bioavailability and mean residence time of propranolol between the two doses. 3. Resting pulse rate was decreased by long acting propranolol 160 mg but not by the lower dose. 4. Both preparations blocked exercise induced tachycardia during the entire observation period of 29 h. Percentage inhibition of exercise tachycardia was significant at all time points but long acting propranolol 160 mg exhibited a greater reduction at 24 h and 29 h. 5. Increase in systolic blood pressure during exercise was inhibited by both preparations during the entire observation period with no differences between them. 6. The doubling of the dose administered was reflected in blood concentrations but not in pharmacodynamic parameters. Few pharmacodynamic differences were found between the two doses.