Carl-Gunnar Regårdh

Clinical Pharmacokinetics of β-Adrenoceptor Blocking Drugs

SummaryAll β-adrenoreceptor blocking drugs seem to be fairly rapidly and completely absorbed from the gastro-intestinal tract. The rate of absorption, however, appears to be lower in elderly patients and possibly also in patients with renal failure than in younger patients.The extent of bioavailability varies considerably between different β-blockers. Some of these drugs (e.g. alprenolol and propranolol) have a low extent of bioavailability due to a high first-pass elimination effect, while pindolol and practolol for example are influenced very little by this effect. However, as some β-blockers form active metabolites, the bioavailability calculated as the ratio between the area under the plasma concentration time curve of unchanged drug after oral and intravenous administration does not give an accurate estimation of the fraction of the biologically active dose reaching the systemic circulation.The β-blockers so far studied are rapidly distributed in the body. The t½ of distribution ranges between 5 to 30 minutes. The apparent volume of distribution varies 3-to 4-fold between the compounds but in all cases the apparent volume of distribution exceeds the physiological body space. In patients with impaired liver function an increase of the volume of distribution of propranolol has been found.The β-blockers are relatively rapidly eliminated from the body and most of them have an elimination half-life between 2 to 4 hours. For atenolol, practolol and Sotalol higher values have been reported. The most lipophilic β-blockers are almost completely metabolised in the liver, whereas those of lower lipophilicity are mainly excreted via the kidneys. Impaired liver and kidney function have been found to significantly influence the rate of elimination of those β-blockers eliminated via the insufficient organ of elimination.Numerous investigators have shown that the β-blocking effect is linearly related to the logarithm of the plasma concentration. In spite of this relationship, it is difficult from mean data to predict the individual plasma concentration which is necessary for a certain degree of β-blockade. This might be due to variations in the quantitative formation of active metabolites, individual differences in the plasma protein binding and rather flat plasma level-response curves.Also with respect to the therapeutic effect, the plasma levels vary considerably between individuals. This limits the value of determination of plasma concentrations in order to adjust the therapeutic dose. Our recommendation is that these facilities should be utilised in selected patient groups, e.g. those who have a poor therapeutic response to a β-blocker although the dose is high, and those patients with impaired renal or liver function.The duration of β-blockade is dose-dependent since the pharmacological effect declines with a constant rate (zero-order kinetics) within relatively wide dosage intervals. The rate of decline is a function of the plasma half-life and the slope of the regression line for the effect versus plasma concentration. This implies that most of the β-blockers can be administered at substantially longer intervals than indicated by their half-lives.

Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects

Twelve Caucasian healthy men and women, of whom six were poor metabolizers (PMs) and six were extensive metabolizers (EMs) of S-mephenytoin, together with 13 Chinese healthy men and women (five PMs and eight EMs), received a single oral 20 mg dose of omeprazole. Plasma levels of omeprazole and its two main metabolites, omeprazole sulphone and hydroxyomeprazole, were determined by HPLC. The mean (+/- SD) area under the plasma concentration-time curve (AUC) for omeprazole was 11.1 +/- 2.6 and 0.9 +/- 0.4 microM h in the Caucasian PMs and EMs, respectively. Corresponding values for elimination half-life were 2.3 +/- 0.4 and 0.7 +/- 0.4 h. In the Chinese PMs and EMs the AUC of omeprazole as 13.3 +/- 5.6 and 2.6 +/- 1.8 microM h. The AUCs of omeprazole were significantly higher in the Chinese EMs than in the Caucasian EMs possibly due to the higher proportion of heterozygotes in the former than in the latter group. The elimination half-life in the Chinese PMs and EMs was 2.4 +/- 0.2 and 0.8 +/- 0.2 h--similar to the observations in the Caucasian subjects. The maximum plasma concentration of hydroxyomeprazole was five-fold and four-fold higher in EMs compared to PMs among Caucasians and Chinese, respectively. The elimination half-life of the hydroxy metabolite was also longer in PMs than in EMs in both populations. The ratio between AUC for omeprazole and AUC for hydroxyomeprazole was 11.9 +/- 2.1 and 0.6 +/- 0.1 in Caucasian PMs and EMs, respectively. Corresponding values in the Chinese were 13.1 +/- 2.9 and 1.6 +/- 0.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Interethnic Differences in Omeprazole Metabolism in the Two S-Mephenytoin Hydroxylation Phenotypes Studied in Caucasians and Orientals

Two independent studies showed that the 5-hydroxylation, but not the sulfoxidation, of omeprazole is more rapid in extensive metabolizers (EMs) than in poor metabolizers (PMs) of S-mephenytoin. In Caucasian, Chinese, and Korean PMs, the mean oral clearances were similar and not significantly different (85, 73, and 59 ml h-1 kg-1, respectively). However, the geometric mean clearance in Caucasian EMs (950 ml h-1 kg-1) was higher than in both Chinese EMs (426 ml h-1 kg-1, p < 0.05) and Korean EMs (446 ml h-1 kg-1, p < 0.01). The incidence of PMs of S-mephenytoin is higher in Chinese (14.6%) and Koreans (12.6%) than in Swedish Caucasians (3.3%). Therefore, the proportion of heterozygous compared to homozygous EMs is higher in Orientals than in Caucasians. This might explain the higher clearance of omeprazole in Caucasian EMs compared to the clearance of omeprazole in Chinese and Korean EMs of S-mephenytoin.

The pharmacokinetics of omeprazole in humans--a study of single intravenous and oral doses.

The pharamacokinetics of omeprazole, hydroxyomeprazole, omeprazolesulfone, and “remaining metabolites” have been studied in eight young healthy subjects following an acute i.v. and oral dose of 10 and 20 mg of 14C-labeled drug, respectively. The oral dose was given as a buffered solution. Two subjects exhibited essentially higher and more sustained plasma levels of omeprazole than the others. This was due to a higher bioavailability, lower clearance, and longer t1/2 of omeprazole in these two subjects. Maximum concentration (0.7–4.6 mUmol/L) was reached between 10 and 25 min after oral dosing. The median bioavailability was 39% (25–117%) and the median systemic plasma clearance was 624 ml/min (range of 59–828 ml/min). The corresponding t1/2 for the i.v. dose was 35 min (16–150 min) and 39 min (14–186 min) after oral administration. The drug was rapidly distributed to extravascular sites (mean t1/2Λ1 = 3.0 \pm 0.8 min). Mean Vss was 0.23 \pm 0.04 L/kg. Low systemic clearance of omeprazole was associated with a decreased formation rate of hydroxyomepraxole and “remaining metabolites” while omeprazole-sulfone formation seemed to be less affected. However, there was a clear-cut correlation between the t1/2 of omeprazole and of its omeprazolesulfone metabolite, indicating that the elimination of these two compounds is mediated by the same isoenzyme. The mean urinary recovery of the radioactive dose during 96 h was 78.3 \pm 2.3 and 75.7 \pm 2.6% for the i.v. and oral dose, respectively. Insignificant amounts were due to unchanged drug and omeprazolesulfone. The excretion of hydroxyomeprazole during the first 12 h varied between 4.6 to 15.5% of a given dose. The mean recovery of radioactivity in the feces was 19.3 \pm 3.1% of a given i.v. dose and 18.2 \pm 2.3% when given orally. It is concluded that omeprazole is mainly eliminated metabolically and that there is a substantial interindividual variation in the rate of formation of primary and secondary metabolites. This variation in omeprazole disposition is probably of limited clinical importance. The half-life, with a maximum of 3 h, is too short to cause accumulation when the drug is administered in a once-daily regimen.

Evidence for an Interaction Between the β-Blocker Pafenolol and Bile Salts in the Intestinal Lumen of the Rat Leading to Dose-Dependent Oral Absorption and Double Peaks in the Plasma Concentration–Time Profile

Pafenolol is a β-blocker with unusual oral absorption properties. The blood concentration–time profile exhibits two peaks, and the bioavailability is low and dose dependent because of incomplete and nonlinear intestinal uptake. We addressed the question whether the intestinal absorption of pafenolol was affected by bile depletion in the gut lumen of rats. Further, the hypothesis that variable gastric emptying accounts for double peaks in blood was tested by duodenal administration of pafenolol. Following intraduodenal administration to rats with intact bile secretion, double peaks were observed in the blood concentration–time curve. The bioavailability was 6.8 ± 0.7% for the low dose (1 µmol/kg) and increased significantly to 28 ± 10% following the high duodenal dose (25 µmol/kg). These blood concentration–time profiles exclude interrupted gastric emptying as cause of the twin peaks. In bile duct-cannulated rats the intestinal absorption of the low dose (1 µmol/kg) was still poor (F = 10.7 ± 5.5%) and the blood concentration–time profile contained two peaks. Following administration of a high duodenal dose (25 µmol/kg) to rats with an almost bile-free small intestine, the absorption rate increased and the double-peak phenomenon disappeared in five of seven rats, while the bioavailability increased significantly, to 62 ± 27%. These results suggest that the low bioavailability of pafenolol is due to a complexation between bile and pafenolol in the gut lumen, preventing intestinal uptake in the major part of the small intestine. Further, such complex formation in the intestinal lumen may be the underlying mechanism of the double peaks observed in the blood concentration–time profile.

Pharmacokinetics of [14C] omeprazole in patients with impaired renal function

Pharmacokinetics of [14C] omeprazole and its metabolites were studied after single intravenous and oral doses of 20 and 40 mg, respectively, to 12 patients with chronic renal insufficiency. Blood samples for determination of total radioactivity, omeprazole, OH‐omeprazole, sulfone, and sulfide were taken for 24 hours. Urine was collected over 96 hours for determination of total radioactivity and during the first 24 hours for additional assay of omeprazole and metabolites. The mean systemic availability was 70%. The mean plasma t1/2 of omeprazole was 0.6 hours. Unchanged omeprazole was not measurable in urine. Derived pharmacokinetic constants of intact omeprazole were within the range of those reported in healthy individuals. The accumulated 24‐hour excretion of radioactive metabolites was related significantly to creatinine clearance. The cumulative excretion of total radioactivity in urine over 96 hours in percent of given dose varied between 25% and 83%.

Pharmacokinetics of metoprolol and its metabolite α-OH-metoprolol in healthy, non-smoking, elderly individuals

SummaryThe absorption and disposition of metoprolol have been evaluated in 10 healthy, non-smoking, elderly individuals (mean age 73.1 years) by simultaneous determination of [3H]-metoprolol and unlabelled metoprolol. The labelled drug was given as an intravenous tracer dose, immediately followed by oral metoprolol 25 mg. The experiment was preceded by administration of metoprolol 25 mg b.i.d. for 3 days. The volume of distribution, elimination half-life and total body clearance were almost the same as previously observed in healthy, young subjects. The mean systemic availability was about 39% in the elderly, which is lower than the mean of 55% observed in a control group of young volunteers who received 50 mg b.i.d. In the elderly, the mean plasma concentration of α-OH-metoprolol was about twice as high as that of the parent drug, whereas the opposite was true of the control group. The results indicate that age-related physiological changes have a negligible effect on the pharmacokinetics of metoprolol.

The Relationship Between Metoprolol Plasma Concentration and Beta1‐Blockade in Healthy Subjects: A Study on Conventional Metoprolol and Metoprolol CR/ZOK Formulations

Four studies using different daily doses (100 mg, 200 mg, 300 mg and 400 mg) have examined the bioequivalence of the once daily formulation metoprolol CR/ZOK and conventional metoprolol tablets (CT). These studies showed metoprolol CR/ZOK to have a similar beta1‐blocking activity to metoprolol CT but that the bioavailability of the new formulation was lower. This paper presents the analysis of data from all four studies, looking at the relationship between plasma concentrations and beta1‐blockade measured as reduction of exercise induced tachycardia.

Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis

SummaryThe pharmacokinetics of omeprazole and its metabolites following single doses were studied in 8 patients with liver cirrhosis. Each patient participated in 2 experiments in which [14C]omeprazole was administered either intravenously (20mg) or in an oral solution (40mg) in a randomised crossover design. Plasma concentrations of omeprazole and 2 of its identified metabolites, as well as total radioactivity were followed for 24h; urinary excretion was followed for 96h.The mean elimination half-life of omeprazole in the patients with cirrhosis was 2.8h and the mean total plasma clearance was 67 ml/min (4.02 L/h); corresponding values from separate studies in young healthy volunteers were 0.7h and 594 ml/min (35.64 L/h). The mean systemic availability was nearly 100% in the patients with cirrhosis whereas the previously reported value in young volunteers was only 56%. Almost 80% of a given dose was excreted as urinary metabolites in both patients and young volunteers. It is concluded that, as the hepatic clearance of omeprazole was substantially reduced in these patients, the dose of omeprazole needed for a certain degree of acid suppression is lower in patients with liver cirrhosis.

Pharmacokinetic and Biopharmaceutic Aspects of Once Daily Treatment with Metoprolol CR/ZOK: A Review Article

In the development of a new controlled release preparation and its subsequent assessment there are a number of factors that need to be considered both related to the drug itself and to the pharmaceutical preparation. This review describes the biopharmaceutical and pharmacokinetic properties of metoprolol CR/ZOK, a recently introduced formulation of a widely used beta1‐selective adrenoceptor antagonist intended for once daily usage.