P. Collste

Distribution and elimination kinetics of carbamazepine in man

SummaryCarbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagonist of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metoprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 ± 3.8 (SEM)/10 ± 2.1 mm Hg in the lying position and 23 ± 4.419 ± 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady‐state plasma concentrations of metoprolol varied 17‐fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p < 0.05) and decrease in exercise tachycardia (r = 0.65, p < 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mglkg. Metoprolol decreased PRA by 67 ± 1.9 and 71 ± 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p < 0.05) but not to the plasma steady‐state levels ofmetoprolol, the degree of beta receptor blockade, and the decrease in PRA.

Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses.

SummaryA gas chromatographic method has been employed to determine chlorthalidone in plasma and whole blood after therapeutic doses. Radioactively labelled chlorthalidone was used for in vitro studies of the uptake of chlorthalidone from plasma by red blood cells. Chlorthalidone was markedly concentrated in red cells and as a compartment they would account for at least 30% of total drug in the body after multiple doses. The ratio between the plasma and red cell concentration of chlorthalidone varied between individuals. After a single oral dose of 50 mg in 6 healthy volunteers chlorthalidone was eliminated with a half-life of 51 to 89 hours. The apparent volume of distribution varied between 3 and 13 1/kg and the clearance between 53 and 145 ml/min. The mean steady-state plasma concentrations during treatment with a standard dose of 50 mg daily (n=10) varied 5-fold between individuals. During the steady state approximately 50% of the daily dose was excreted unchanged in the urine during 24 hrs. The plasma levels observed in patients were higher than those predicted from the single oral dose studies in healthy volunteers.

Steady-state plasma concentrations of alprenolol in man

SummaryPlasma concentrations of alprenolol during one inter-dose interval and steady-state plasma concentrations have been determined in 30 patients treated for a prolonged period. The latter varied 25-fold between patients who received identical doses. Peak plasma concentrations were achieved at similar times in different patients, but only the level 5–7 h after administration was well correlated (r=0.997) with the steady-state concentration. The type of pharmacokinetic analysis described here is recommended for studies of the relationships between plasma concentration and effects of drugs with short half-lives.

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension

SummaryMean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 — 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r=0.80, p<0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the β-blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r=0.79, p<0.001).

Plasma levels and effects of metoprolol after single and multiple oral doses

Five patients with moderate hypertension were given placebo and at least 3 single oral doses (25, 50, 75, 100, or 150 mg) of metoprolol as well as multiple doses at at least 2 dose levels (25, 50, or 100 mg thrice daily). Blood pressure, pulse rate at rest, plasma renin activity, and drug plasma concentration were intensively monitored during 7.5 hr after each dose. Pulse rate, systolic blood pressure, and plasma renin activity decreased after the single oral doses, but diastolic blood pressure did not decrease consistently. The correlation coefficients between percentage decrease in systolic blood pressure and pulse rate and total plasma concentrations were higher individually than in the group. The corresponding regression equations were different between individuals and for systolic blood pressure there was a 700% difference in regression coefficients. The acute changes in diastolic blood pressure and plasma renin activity were not related to metoprolol plasma concentrations. The decrease in systolic blood pressure and pulse rate on multiple doses could not be predicted from the response after single doses.

Influence of pentobarbital on metoprolol plasma levels

Induction of microsomal enzymes with barbiturates in rats has little effect on the metabolism of metoprolol, compared with propranolol and alprenolol, which undergo extensive hepatic extraction in animals and man. Our study was designed to examine whether the metabolism of metoprolol is inducable by barbiturate in man. In 8 healthy subjects the area under the plasma concentration/time curve after 0.1 gm metoprolol was reduced by a mean of 32% after treatment with 0.1 gm pentobarbital at bedtime for 10 days. There was considerable interindividual variability in the reduction after pentobarbital treatment (2% to 46%).

Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxy-alprenolol.

Six healthy subjects were given placebo and a single oral 0.2‐gm dose of alprenolol (Aptin) before and after 0.1 gin pentobarbital at bedtime for 10 days. The plasma concentrations of alprenolol and its metabolite 4‐hydroxy‐alprenolol and the inhibition of exercise tachycardia were studied for 7 hr after the alprenolol. Alprenolol and 4‐hydroxy‐alprenolol plasma levels were decreased by about 40% by pentobarbital but plasma half‐lives were unchanged. The inhibition of exercise tachycardia during a 7‐hr period was reduced from 14.0% to 10.7% by pentobarbital. The reduction was proportional to the decreased drug plasma levels. There was a significant contribution of the metabolite to alprenolol effect. The estimation of relative potency of metabolite against parent compound was 0.9 before pentobarbital and 1.9 after pentobarbital.

Contribution of 4‐hydroxy‐alprenolol to adrenergic beta receptor blockade of alprenolol

Alprenolol, like propranolol, is metabolized to a 4‐hydroxy derivative. This study was performed in 6 human volunteers to determine the potency of the metabolite in relation to that of alprenolol with respect to reduction of exercise‐induced tachycardia. The metabolite reached higher plasma levels than alprenolol during the first hours after both single and repetitive oral doses of alprenolol but was not detected in plasma after an intravenous dose. The plasma elimination half‐life for 4‐hydroxy‐alprenolol was one‐third that for alprenolol (0.8 hr and 2.5 hr, p < 0.01). Percentage reduction of exercise heart rate and total plasma levels of alprenolol after a 10‐mg intravenous dose correlated (r = 0.56, p < 0.01). This was generally higher within individuals, since the responsiveness to unchanged alprenolol differs among subjects. The effect‐concentration relationship was slightly higher (r = 0.67) when non‐protein‐bound alprenolol was substituted for total alprenolol. 4‐Hydroxy‐alprenolol contributed to the effect after oral administration of alprenolol; total plasma levels were equipotent with alprenolol. It is concluded that the contribution of the metabolite to effect varied among individuals and was dependent on mode of administration (intravenous or oral), dose, and time after dosage. We also introduce an approach to the evaluation of the activity of drug metabolites in the presence of the parent compound.

Time course of blood pressure, pulse rate, plasma renin and metoprolol during treatment of hypertensive patients

SummaryEleven patients were treated for essential hypertension with metoprolol (Selokén®) for more than three months. The time course of changes in blood pressure, pulse rate and plasma renin activity was studied during treatment with an oral maintenance dose of 100 mg twice daily. Significant decreases in pulse rate, diastolic blood pressure and plasma renin activity were observed even after the first dose. The plasma concentration of metoprolol reached equilibrium after the second dose. After the third dose there was no further significant change in blood pressure. There was a significant correlation (p<0.001) between the initial (after three doses) and final (after >90days) effect of metoprolol on blood pressure (r=0.86 and 0.91 for systolic and diastolic blood pressure change, respectively).