Plasma and synovial fluid concentrations of diclofenac sodium and its hydroxylated metabolites during once-daily administration of a 100 mg slow-release formulation.

Plasma and knee joint synovial fluid (SF) concentration of diclofenac sodium and its hydroxylated metabolites were measured after chronic dosing with the 100 mg polymer matrix formulation. Peak concentrations were reached in plasma and SF roughly after administration. Plasma concentrations then fell rapidly, but concentrations in SF were maintained for up to 25 h. The active metabolite was present in both fluids throughout the study period. The slow-release form showed a longer plasma/SF equilibration time than the conventional tablet had in a previous study. Prostaglandin E1 and F2 alpha concentrations were lower in the early post-dose period but did not correlate with drug concentrations.

Baclofen in the elderly stroke patient its side-effects and pharmacokinetics.

A double blind crossover trial of baclofen against placebo in elderly stroke patients was discontinued because the drug produced an unacceptably high level of drowsiness. In a subsequent study baclofen 10 mg was given orally to 12 elderly stroke patients, and drug concentrations measured from a series of plasma samples. A group of healthy subjects given the same dose in a previous study were used as controls. Elderly patients took longer to achieve peak plasma baclofen concentrations, but healthy controls had higher peak values and eliminated the drug more rapidly; areas under the curve were similar in the two groups. Simulations based on mean data suggest that increased drowsiness in the elderly was probably not due to changes in the drug's pharmacokinetic behaviour.

Gastrointestinal transit of Oros drug delivery systems in healthy volunteers: a short report.

Transit times for oxprenolol and metoprolol Oros drug delivery systems through the gastrointestinal tract have been measured in 35 individuals in six separate studies. A total of 45 systems were recovered in a median time of 27.4 h; individual transit times varied from 5.1 to 58.3 h. The residual amount of drug in recovered systems was inversely related to transit time and corresponded closely with the amount estimated from in vitro dissolution profiles.

Influence of site of drug delivery on the systemic availability of metoprolol: comparison of intragastric infusion and 14/190 Oros administration.

The influence of the site of drug delivery on the systemic availability of metoprolol has been evaluated by measuring plasma drug concentrations in six healthy volunteers after administration of a continuous 13.5 h intragastric infusion and a 14/190 Oros controlled-release dosage form, on two separate occasions. The same total amount of drug was administered at the same rate on both occasions but the Oros system moved through the gut whereas the site of the infusion was constant. The differences between treatments were confined largely to the period 6-15 h after dosing when lower plasma concentrations were obtained after administration of the Oros system. The levels after 20 h were higher for Oros, however, reflecting its longer duration of drug release. The amount of drug reaching the circulation was 19.8% less for the Oros preparation compared with intragastric infusion but this was not due to incomplete release since the residual amounts of drug in three systems recovered from faeces corresponded to less than 12% of the administered dose. Analysis of the plasma profiles by the Wagner-Nelson method indicated a reasonable agreement between in vitro release and in vivo absorption. The appearance of drug in plasma was delayed for both treatments, and for Oros the apparent absorption rate slowed 6 h after dosing. Plasma profiles after 14/190 metoprolol Oros were consistent with prolonged in vivo delivery and absorption from the gut. The absorption process, however, was associated with some reduction both in the rate, after 6 h, and in the total amount reaching the circulation.

Comparison of single-dose pharmacokinetic and pharmacodynamic properties of two metoprolol Oros systems with different initial zero-order release rates.

Plasma concentrations and haemodynamic effects at rest and during exercise have been measured in six healthy volunteers after single oral dosing with two Oros drug delivery systems containing 190 mg metoprolol fumarate but with initial release rates of 14 and 19 mg/h, respectively. Sub-maximal exercise heart rates were attenuated by both Oros systems throughout most of the 30 h study period but no significant differences were detected between the 14/190 and 19/190 forms. Resting pulse rates and blood pressure were similarly affected by the Oros preparations. Approximately the same amount of drug reached the circulation from the Oros systems, but the 19/190 form produced higher peak concentrations at earlier times after dosing. At 24 h higher plasma concentrations were observed for the 14/190 preparation, reflecting its longer duration of drug release. There was no apparent advantage of one form over the other as regards haemodynamic response. The reduced peak plasma concentration with 14/190 Oros may, however, be an advantage in terms of tolerability.

A multiple dose pharmacokinetic and pharmacodynamic evaluation of conventional and 19/285 Oros formulations of metoprolol in healthy volunteers.

Plasma metoprolol concentrations and haemodynamic effects have been measured in six healthy male volunteers during once daily dosing with a 19/285 Oros system and twice daily dosing with 100 mg conventional tablets, on two separate occasions. Plasma drug concentrations throughout the day varied less with the Oros than with the conventional tablet regimen. Predosing concentrations were also higher with Oros but areas under the curve, after correcting for the differences in dose, were similar for the two preparations. Inhibition of exercise tachycardia was drug concentration dependent and was smoothly controlled through the day only with the Oros preparation. Predosing effects at steady-state were also greater for the Oros regimen. The decline in mean blood pressure, however, showed the same daily pattern for both regimens, and no significant differences were detected between Oros and conventional tablet treatments. The smoothness of the plasma profiles after Oros confirmed the controlled-release performance of the system in vivo and indicates its potential in the treatment of angina, cardiac arrhythmias and wherever it is important not to jeopardize steady selective beta-adrenoceptor blockade.

Efflux of 86Rb from rat and mouse pancreatic islets: the role of membrane depolarization.

The efflux of 86Rb from rat or mouse perifused islets preloaded with the isotope has been used as an index of the potassium permeability of the islet beta-cell membrane. Cellular transmembrane potentials were altered by changing [K]O or by direct electrical stimulation and the effects on potassium permeability examined. Omission of KCl from the medium perifusing rat islets induced a biphasic change in 86Rb efflux, a brief decline being superseded by a pronounced increase in efflux. Re-introduction of KCl, 4.7 mM, caused a further increase in 86Rb efflux preceding a return to control values. Increasing [K]O from 4.7 mM to 10 mM, 20 mM or 47 mM caused a phasic increase in 86Rb efflux with the magnitude of both the peak and average rate of efflux being dependent upon the extent of the change in [K]O. The increase in 86Rb efflux produced by [K]O, 47 mM, was attenuated by Co2+, 2.56 mM (51% inhibition) or quinine, 10 microM (47% inhibition), but efflux remained significantly (P less than 0.001) above control values. Electrical stimulation of single microdissected mouse pancreatic islets by currents of 0.1 to 0.5 mA evoked a rapid, phasic increase in 86Rb efflux. The magnitude of the response was unaffected by EGTA, 2 mM, or nupercaine, 100 microM. These observations are discussed in relation to the mechanisms controlling the potassium permeability, membrane potential and insulin secretion of the pancreatic islet beta-cell. It is concluded that beta-cell depolarization by a raised [K]0 increases potassium permeability and efflux by at least two mechanisms: (i) a calcium-dependent potassium efflux triggered by an increase in [Ca]i and (ii) an activation of voltage-sensitive potassium channels which occurs even when the calcium-dependent potassium permeability is blocked.

The control of 86Rb efflux from rat isolated pancreatic islets by the sulphonylureas tolbutamide and glibenclamide.

The efflux of 86Rb from rat isolated pancreatic islets preloaded with the isotope and perifused in vitro, has been used to monitor the effects of sulphonylureas on the potassium permeability, Pk, of pancreatic beta-cells. Tolbutamide (5 microM to 5 mM) had a dual effect, causing initially a decrease in 86Rb efflux (the 'on' response) which was rapidly superseded on drug removal by a large phasic increase in 86Rb efflux (the 'off' response). Each kinetic response had a different dose-dependency: the 'on' response was half-maximal at tolbutamide concentrations of 0.02 mM, maximal at 0.2 mM and decreased by concentrations greater than 0.2 mM whereas the 'off' response was half-maximal at 0.07 mM, maximal at 0.7 mM, with further increases in concentration (up to 5 mM) causing no further change in magnitude. Analysis of the time- and concentration-dependency of tolbutamide action, by presenting increasing concentrations (0 to 1.4 mM) of tolbutamide as a ramp or step function, established a critical dependence of the kinetics of 86Rb efflux during and after exposure to tolbutamide upon the initial rate of increase of the tolbutamide concentration rather than its final steady state. In the presence of quinine (10 microM), D600 (50 microM), or tetraethylammonium (20 mM), the secondary increase in 86Rb following tolbutamide (0.7 mM) removal was totally inhibited. Co2+ (2.56 mM) not only blocked the secondary 'off' response but also potentiated the initial 'on' response of tolbutamide. Glibenclamide produced a rapid decrease in 86Rb efflux but at a much lower concentration (10 microM) than tolbutamide and with no 'off' response apparent over a wide range of concentration (1 to 100 microM); moreover the decrease in 86Rb efflux was sustained and only slowly reversible. It is concluded that tolbutamide has two opposing actions on islet beta-cell 86Rb efflux, and therefore PK: (i) a tendency to increase a calcium-sensitive PK by stimulating calcium entry into the cell and (ii) a decrease in PK that may be due to a direct effect on the calcium-sensitive PK itself. The more sustained pharmacological action of glibenclamide is explained by the longer-lasting decrease in PK that it produces.