D. B. Jack

The influence of food on the absorption of diclofenac after single and multiple oral doses.

SummaryA single dose of enteric-coated diclofenac sodium was taken fasting and immediately after a standard breakfast by twelve healthy volunteers. A considerable delay in the onset of absorption was observed, non-fasting, varying from 2.5 to 12 h compared with 1.5 to 2.75 h when fasting. Peak plasma concentrations were reduced after food but areas under plasma concentration-time curves were comparable. Six subjects then took part in a study involving single and repeated dosing under fasting and non-fasting conditions. As before, prolonged and variable delays were observed when the enteric-coated tablets were taken after food. On repeated dosing, maximum plasma concentrations were reached after 6 h non-fasting compared with 2.5 h fasting. Peak plasma levels were, however, similar.

Variability of beta-blocker pharmacokinetics in young volunteers

SummaryPlasma concentrations of metoprolol, propranolol oxprenolol, acebutolol and its metabolite diacetolol were measured after single oral doses in young healthy volunteers. In order to assess the inter-and intra-subject variability the following pharmacokinetic parameters were compared: AUCo24, Cmax, tmax and t1/2. The smallest variation in inter-subject variability was seen with oxprenolol and acebutolol: intrasubject variability was more uniform. Female volunteers taking an oral contraceptive generally had higher AUCo24 and Cmax values than those not. This finding reached statistical significance only for metoprolol AUCo24.

A study of the effect of aspirin on the pharmacokinetics of oral and intravenous diclofenac sodium

SummaryPrevious studies have shown that aspirin interacts with orally administered diclofenac sodium, causing reduced peak concentrations, lower levels and decreased areas under curves. In this study, diclofenac sodium was administered orally and intravenously with and without aspirin, to 6 healthy female volunteers. After intravenous dosing both plasma levels and areas under curves were significantly reduced although none of the rate constants was affected. The volume of distribution of diclofenac was increased as was the plasma clearance. Oral administration with aspirin also resulted in lower plasma levels, particularly peak levels, and areas under curves. Comparison of AUCs for both modes of administration with and without aspirin suggested that lower levels after oral administration were not due to impaired absorption. These observations are best explained by decreased protein binding and increased biliary excretion of diclofenac in the presence of salicylate.

The intra- and inter-subject variability of Nifedipine pharmacokinetics in young volunteers

SummaryPlasma concentrations of Nifedipine were measured following single oral doses of Nifedipine Slow Release (Adalat Retard) on three separate occasions to young, healthy volunteers of both sexes. Intra- and inter-subject variability were assessed by comparing the pharmacokinetic parameters, AUC, Cmax and T50%AUC. Interindividual variability was less than that observed in other studies with the betablockers, metoprolol and propranolol and there was no evidence of differences between the sexes.

The pharmacokinetics of diclofenac sodium in patients with active rheumatoid disease

SummaryPharmacokinetic data for diclofenac sodium has been well established in healthy volunteers, whereas in patients with rheumatoid arthritis very little information is available in the literature. A single oral dose of enteric-coated diclofenac sodium was given to 10 patients with active rheumatoid disease, adopting the same procedures used for a group of 10 healthy volunteers in whom pharmacokinetic data was already available. Plasma specimens were collected over a period of 8h following administration and concentrations of diclofenac determined by GLC. Resulting plasma concentration curves were similar to those obtained in the healthy subjects in that areas under curves and terminal half-lives were comparable. However, peak concentrations of diclofenac were significantly reduced in the rheumatoid patients. The lower peak concentrations were correlated with the lower serum albumin levels in the patients which are associated with active rheumatoid disease.

The influence of food on the absorption of diclofenac as determined by the urinary excretion of the unchanged drug and its major metabolites during chronic administration

SummarySix healthy subjects took diclofenac as an enteric-coated preparation twice daily for 17 days under the following conditions: (i) fasting, (ii) 15 min before a meal, and (iii) immediately after a meal. Urine specimens were collected on two separate days of each regimen and diclofenac and its total monohydroxylated metabolites measured. Statistical analysis of the excretion of diclofenac and its metabolites showed that, during chronic administration, absorption was not significantly influenced by dosing before or after food. The absorption pattern after both these modes of administration was comparable to that obtained under fasting conditions.

Pharmacokinetics and pharmacodynamics of isradipine (PN 200-110) in young and elderly patients

Abstract Isradipine (PN 200-110) was given to eight young and nine elderly mildly hypertensive patients. Pharmacokinetic and pharmacodynamic studies were carried out after a single 5 mg dose and after three weeks dosing with 5 mg twice daily. Isradipine lowered blood pressure and was well tolerated. Plasma concentration time profiles were not significantly different in young and elderly patients. Changes in blood pressure were similar in both groups. Unlike other dihydropyridines, short-term administration of isradipine did not cause tachycardia.

THE INFLUENCE OF BETA‐ADRENOCEPTOR BLOCKADE ON THE LIPOLYTIC RESPONSE TO EXERCISE

The influence of β‐adrenoceptor blockade on the free fatty acid (FFA) response during and after submaximal exercise was studied in a group of normal volunteers. The study showed that the exercise‐induced rise in serum FFA concentrations seen with placebo was reduced after pretreatment with propranolol. Furthermore, the palmitic, stearic, oleic and linoleic acid responses showed progressive attenuation with increasing doses of propranolol. Different β blockers were studied using comparablc doses: metoprolol and nadolol had little effect and produced FFA profiles that were similar to placebo whereas the changes on pindolol were comparable with those on propranolol.

Pharmacokinetic interactions between felodipine and metoprolol

SummaryThis double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period.Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated.None of the felodipine pharmacokinetic variables (tmax, Cmax, Cmin, AUC (0–12) and t1/2) changed significantly when felodipine and metoprolol were given in combination. Cmax and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although tmax, Cmin and t1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.

Inter- and intra-subject variability of nitrendipine and the effects of food

SummaryPlasma concentrations of nitrendipine were measured, after single (20 mg) oral doses, in young healthy volunteers.On three occasions the subjects ingested the dose having fasted overnight. Data from these three occasions were used to assess variability in nitrendipine pharmacokinetics and both inter- and intra-subject variability were high.On a fourth occasion, the subjects took the tablet after a standard meal.The effects of food on nitrendipine pharmacokinetics, based on the comparison of data from the first fasting visit and the food visit, were negligible.