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.     

The influence of age and smoking on the elimination of disopyramide.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.     

The effect of age on plasma levels of propranolol and practolol in man.

1. Plasma levels of propranolol and practolol were measured in groups of elderly and young subjects, after the oral administration of propranolol (40 mg) and practolol (200 mg) on separate occasions. 2. At all sampling times the mean plasma propranolol level in the group of elderly subjects was substantially greater than the corresponding level in the group of young subjects, there being a significant difference between the two, and a fourfold difference in the mean peak levels. 3. After practolol, there was no significant difference between the mean plasma concentrations of the drug in the two groups for the first 2 hours. Subsequently, the mean plasma levels in the group of elderly subjects were somewhat higher than the corresponding levels in the young group, the differences between the two reaching significance. 4. It is suggested that there is a need to substantially reduce the dose of propranolol given to elderly patients. With practolol, however, no reduction is necessary providing renal function is normal for the patient's age.     

Vitamin C concentration in plasma and leucocytes of men related to age and smoking habit.

Morning plasma and leucocyte vitamin C concentrations were measured in 178 healthy men aged 17-68 years. In the youngest age group (17-29 years), smokers had significantly lower plasma (P less than 0.01) and leucocyte (P less than 0.001) vitamin C levels than non-smokers. With advancing age plasma and leucocyte vitamin C levels of non-smokers appeared to decline. The lower levels in younger smokers did not significantly alter in the later decades. There was no significant difference between the plasma or leucocyte vitamin C levels of smokers and non-smokers in the decade 60-69 years.     

The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.

Steady state metabolite/parent drug plasma ratios were measured in 15 epileptic patients on carbamazepine (CBZ) monotherapy and in seven patients treated with CBZ and clobazam (CLB). CBZ plasma concentrations did not differ between the two groups but patients also treated with CLB exhibited higher concentrations of CBZ-10,11-epoxide (CBZ-E) and trans-10,11-dihydro-10,11-dihydroxy-CBZ (CBZ-T). Ratios between all of the metabolites of CBZ and the parent compound were higher in patients on polytherapy but the ratio between metabolites was not different. CLB comedication causes a moderate increase (about 1.5-fold) in CBZ metabolism, probably by inducing its epoxidation.     

The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers.

1. Plasma binding of tritium-labelled racemic propranolol (P) was measured by equilibrium dialysis. The unbound enantiomers were separated by h.p.l.c. after chiral derivatization. The binding of (-)-P was higher than that of (+)-P. 2. Contrary to previous suggestions, a sex difference in the plasma binding of the P enantiomers (9 young women, 12 young men) was not observed. The unbound percentage of (-)-P was 9.2 +/- 1.8 (mean +/- s.d.) in women vs 9.1 +/- 1.7 in men; for (+)-P it was 10.8 +/- 1.8 vs 10.8 +/- 2.1. 3. In the nine women, the binding did not change with fluctuating plasma oestradiol concentrations during the menstrual cycle. Testosterone cypionate doubled the circulating concentrations of testosterone in eight men but had no effect on P binding. 4. Ethinyl oestradiol (50 micrograms day-1) alone or together with norethindrone (OCD) in eight of the women produced an increase in the unbound percentage of both (-)-P (11.4 +/- 2.6 vs 9.5 +/- 1.6 for control; P < 0.001) and (+)-P (13.2 +/- 2.5 vs 11.2 +/- 1.5 for control; P < 0.001). This was due to a decrease in the plasma concentrations of alpha 1-acid glycoprotein from 0.54 +/- 0.11 mg ml-1 in control to 0.37 +/- 0.08 mg ml-1 (P < 0.001) during ethinyl oestradiol treatment. 5. Enantioselectivity in the unbound fraction of P increased with increasing total binding from a (-)/(+)-ratio of 0.93 at 84% binding to a (-)/(+)-ratio of 0.78 at 94% binding (P < 0.001).     

Pharmacokinetics and plasma steady state levels of doxycycline in undernutrition.

1 The kinetics of doxycycline were studied in well nourished and undernourished male subjects. 2 The area under the curve after an intravenous dose was reduced and total body clearance was significantly elevated with a shorter/beta-phase half life of the drug in undernourished subjects. 3 The percentage of total drug excreted in urine in 48 h and renal clearance of the drug were similar in both groups. 4 Plasma protein binding was significantly reduced and gamma-glutamyltransferase levels tended to be higher in the undernourished as compared to normals. 5 Increased total body clearance of the drug appeared therefore to be due to higher metabolism of drug in undernourished subjects. This increased metabolism is probably due to lower protein binding of the drug and/or induction of drug metabolism. 6 Plasma Cmin concentrations of doxycycline determined at steady state were lower in undernourished subjects. However, they were within the therapeutic range. 7 The observed alterations in kinetics of doxycycline therefore do not warrant a change in dosage regimen in undernourished subjects.     

Effects of grapefruit juice and smoking on verapamil concentrations in steady state

OBJECTIVE: Human gut wall cytochrome P(450) (CYP)3A4 is inhibited by grapefruit juice (G), whereas smoking increases CYP1A2 activity. Both enzymes contribute to verapamil biotransformation. This study was performed to quantitatively assess the effect of these factors on verapamil pharmacokinetics in steady state. METHODS: Twenty-four young healthy volunteers of both sexes (12 smokers, 12 non-smokers) participated in this randomised crossover study. Prolonged release verapamil (120 mg, Isoptin KHK) was given bid for 7 days in two periods. During days 5-7, 1 l of either G or water was coadministered daily. On day 7, concentrations of verapamil and norverapamil enantiomers were determined during one dosing interval, and model independent pharmacokinetic parameters were estimated. PR intervals were monitored for pharmacodynamics. Statistical evaluation was done essentially using bioequivalence methods. RESULTS: G significantly increased ( R, S)-verapamil the area under the concentration-time curve at steady state (AUC(tau,ss)) by a mean of 1.45-fold [90% confidence interval (CI) 1.29, 1.63] and peak plasma concentration at steady state (C(max,ss)) by 1.63-fold (90% CI 1.38, 1.91). The increase in concentrations present for ( R)- and ( S)-enantiomers was slightly greater for verapamil than for norverapamil. Smokers had significantly lower AUC(tau,ss) and C(max,ss) values than non-smokers by (means) 0.61-fold to 0.85-fold for verapamil and norverapamil enantiomers, respectively. G effects were unrelated to naringenin pharmacokinetics. Prolongation of PR intervals by G coadministration was borderline significant; an increase above 350 ms occurred in two individuals during the G period. Significantly increased urinary 6-beta-hydroxycortisol excretion by G suggests induction of hepatic CYP3A. CONCLUSIONS: Patients on verapamil treatment should abstain from grapefruit juice. Smoking habits should be considered for verapamil dosing.     

Comparative trial of propranolol and practolol in hyperthyroidism.

The possible role of practolol in the management of hyperthyroidism has been studied by comparing it with propranolol. 2. In a double-blind cross-over trial, propranolol (40 mg), practolol (120 mg) and a placebo four times daily for one week were compared in twenty-one hyperthyroid patients by sequential analysis. 3. Judged by their effect on the symptoms and signs of thyrotoxicosis, both propranolol and practolol were significantly better than the placebo but no clear distinction could be made between the two active compounds. 4. Propranolol and practolol reduced heart rate by 24 and 17% respectively compared with placebo. 5. Patients generally preferred propranolol or practolol to placebo but this preference did not achieve significance with either drug. 6. Only in its effect on heart rate was practolol significantly inferior to propranolol, and it would appear to be a useful alternative to propranolol in the management of the peripheral manifestations of hyperthyroidism.     

Comparative trial of atenolol and propranolol in hyperthyroidism.

1 The use of atenolol, a cardioselective beta-adrenoceptor antagonist, in the management of hyperthyroidism has been studied by comparing it with propranolol. 2 In a double-blind cross-over trial, atenolol (50 mg), propranolol (40 mg) and placebo 4 times daily for 1 week were compared in twenty-one hyperthyroid patients by sequential analysis. 3. Patients generally preferred atenolol or propranolol to placebo but this preference only achieved significance with propranolol. 4 Judged by their effect on the symptoms and signs of hyperthyroidism, both atenolol and propranolol were significantly better than placebo, but no distinction could be made between the two active compounds. 5 Atenolol and propranolol reduced mean heart rate by 29.8 and 27.1% respectively compared with placebo. 6 Atenolol appeared almost equally effective to propranolol in the management of the peripheral manifestations of hyperthyroidism.     

The effects of age and smoking on the plasma protein binding of lignocaine and diazepam.

In 63 healthy ambulant subjects 18 to 88 years of age, the plasma protein binding of diazepam (principally bound to albumin) decreased with age. Diazepam binding in plasma correlated positively with plasma albumin concentration which also decreased with age. In contrast, the plasma protein binding of the basic drug, lignocaine (predominantly bound to alpha 1-acid glycoprotein [AAG]), tended to increase slightly with age. Lignocaine binding in plasma correlated positively with plasma AAG concentration which also increased slightly with age. Smoking did not affect the plasma protein binding of diazepam or lignocaine or the plasma concentrations of albumin, AAG or nonesterified fatty acids. These results suggest that age-related changes in plasma protein binding of lignocaine and diazepam are determined in part by age-related changes in the concentrations of the binding proteins in plasma. The ageing process alone causes only small changes in the plasma protein binding of these drugs compared with the effect of disease states, however.     

Relationship between plasma propranolol concentration and dose in young, healthy volunteers

The relationship between dose and bioavailability of propranolol was determined in 12 healthy male subjects. The doses employed were 10, 40, 80 or 160 mg of propranolol HCl given three times daily for 4 days. Daily minimum plasma levels showed that there was no accumulation of the drug. In all subjects, non-linear relationships were observed between peak plasma level, or area under the plasma concentration-time curve, and dose. The between subject variation of these parameters was not dose related.     

Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients.

The effects of smoking, CYP2D6 genotype, and concomitant use of enzyme inducers or inhibitors on the steady state plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were evaluated in 92 schizophrenic inpatients. All but three of these patients received concomitant medication, in many cases with drugs potentially interacting with HAL. Of the 92 patients, 63 were treated orally with HAL in a daily dose of 0.4 to 50 mg; 29 patients were treated intramuscularly with a daily equivalent dose of HAL decanoate (expressed as HAL) of 1.8 to 17.9 mg. A wide interindividual variation in HAL dose and in steady state plasma concentrations of HAL and RHAL was observed. In the patients treated orally, the daily oral dose was about 4 times higher and the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers (n = 40) than in nonsmokers (n = 23) (p < 0.01). The dose-normalized RHAL (but not HAL) plasma concentrations and the RHAL/HAL ratio were significantly higher in poor metabolizers (PMs) than in extensive metabolizers (EMs). There was a trend toward an effect of potentially interacting drugs (inducers or inhibitors) on dose, dose-normalized HAL and RHAL plasma concentrations, and the RHAL/HAL ratio. In the patients treated intramuscularly, the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers than in nonsmokers, but no differences in doses were observed. This naturalistic study of modest sample size in a polymedicated population shows an effect of smoking and CYP2D6 genotype (and to a lesser extent, of interacting drugs) on the kinetics of HAL.     

The influence of food on the pharmacokinetics of ''biphasic'' nifedipine at steady state in normal subjects.

Previous studies following single dose administration have suggested that the pharmacokinetics of various nifedipine formulations could be influenced by the timing of associated food consumption. In order more closely to reflect the clinical situation we have carried out a study at steady state using a 'biphasic' formulation comprising 'rapid' and 'retarded' drug release components. Fifteen normal subjects took 20 mg 'biphasic' nifedipine 12 hourly for 10 days. Studies were carried out on days 4, 7 and 10. On these days the nifedipine was taken 2 h or 1 h before or immediately following a light breakfast. A light breakfast influenced neither the rate nor the extent of nifedipine absorption nor the rate or extent of major metabolite appearance. We conclude that at steady state the timing of a light meal is unlikely to alter in any clinically important manner the pharmacokinetics of nifedipine released from 'biphasic' tablets.     

The influence of vancomycin concentration and the pH of plasma on vancomycin protein binding.

A review of numerous studies of the protein binding of vancomycin suggests major discrepancies among their results. The reported percent protein binding of vancomycin varies from 0% to 98%. The influence of pH and concentration on the protein binding of vancomycin was investigated in this study. There was a significant difference (p < 0.001) in percent protein binding in vancomycin-spiked plasma samples across the pH range of 7.0-8.0. There was no significant difference (p > 0.05) in percent protein binding in vancomycin-spiked plasma samples across the concentration range of 2-80 mg/L. It is likely that some of the variation reported to date may be due to a lack of control of pH during the measurement of protein binding of vancomycin.     

Pharmacokinetics of propranolol and sotalol in hyperthyroidism

Summary The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p<0.05) and its clearance was increased (p<0.005), whereas there was no difference in its serum t_1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.