Jan H. G. Jonkman

Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers.

The study was conducted in healthy male volunteers to evaluate the absorption, metabolic pattern, and mode of elimination of telmisartan, a nonpeptide angiotensin II receptor antagonist. [14C]telmisartan was administered orally in solution as a single 40 mg dose to 5 subjects. A further 5 subjects received short‐term intravenous infusion of [14C]telmisartan 40 mg. Measurement of total 14C radioactivity in plasma showed that about 50% was absorbed following oral administration, with maximum plasma concentration observed after 0.5 to 1 hour. Absolute bioavailability was 43%. On average, 84% of total radioactivity in plasma reflected the parent compound. The remainder of total radioactivity could be ascribed to the glucuronide conjugate of telmisartan, which represented the only metabolite in man. About 99.5% of telmisartan was bound to plasma protein, mainly to albumin and α‐1‐acid glycoprotein. Telmisartan was reversibly distributed into erythrocytes. More than 90% of administered dose was excreted within 120 hours, and the excretion balance was complete 144 hours after dosing. Radioactivity was almost exclusively (> 98%) excreted via the feces; urinary excretion accounted for < 1% of the dose, irrespective of the route of administration. In the small fraction excreted into urine, the glucuronide conjugate of telmisartan was predominant. Although some telmisartan glucuronide was detected in plasma, only unchanged drug was identified in the feces. No changes in vital signs, electrocardiogram, or clinical laboratory tests were detected following telmisartan administration, and adverse events, predominantly unrelated to treatment and of mild intensity, were infrequent. One subject fainted and, on another occasion, reported faintness; these events were probably due to the antihypertensive action of the intravenous study medication.

Absorption, metabolism and excretion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing

AbstractObjective: The present study was designed to assess the disposition of 14C-repaglinide in whole blood, plasma, urine and faeces, and to measure the total recovery of drug-related material in urine and faeces after a single 2-mg oral dose of 14C-repaglinide during multiple dosing. Methods: In this single-centre, open-label, phase-I trial, six healthy male volunteers received 2 mg of the prandial glucose regulator, repaglinide, four times daily for 13 days, 15 min before meals. On the morning of day 7, breakfast was omitted and the dose was given as an oral solution containing 2 mg of 14C-repaglinide. Results: After oral dosing, a mean peak plasma concentration of repaglinide of 27.74 ng · ml−1 (range: 16.84–36.65 ng · ml−1) was observed with a time to peak concentration of 0.5 h. Approximately 20% of repaglinide and its associated metabolites were distributed into red blood cells. No measurable 14C-radioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with 14C-repaglinide, 90% of the administered dose appeared in the faeces and 8% was excreted in urine. In the plasma, the major compound was repaglinide (61%). In the urine, the major metabolites were unidentified polar compounds, the aromatic amine (M1) (24%), and the dicarboxylic acid (M2) (22%). In the faeces, the major metabolite was M2 (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite of repaglinide in humans was M2. During regular dosing for 6 days, the morning plasma trough levels of repaglinide were, with very few exceptions, almost always too low to measure, indicating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well tolerated, and there were no episodes of hypoglycaemia. Conclusion: After oral dosing with repaglinide, the mean peak plasma concentration was rapidly attained and, thereafter, plasma concentrations decreased promptly. The major route of excretion was via the faeces. These properties make repaglinide a suitable insulin secretagogue for all patients with type-2 diabetes who retain sufficient β-cell function.

Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH(1-84)] in healthy postmenopausal volunteers

Parathyroid hormone [PTH(1–84)] is intended for treatment of osteoporosis because it stimulates new bone formation of normal structure and composition. Recently, recombinant human PTH(1–84) [rhPTH(1–84)] has become available for therapeutic evaluation.

A Comparison of the Pharmacokinetics and Tolerability of Riluzole after Repeat Dose Administration in Healthy Elderly and Young Volunteers

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender‐ and weight‐matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half‐life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.

The Effect of Telmisartan on the Steady‐State Pharmacokinetics of Digoxin in Healthy Male Volunteers

A multiple‐dose, open‐label, two‐period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple‐dose telmisartan on the steady‐state pharmacokinetics of digoxin. On day 1 of a 7‐day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7‐day medication period was separated by a washout period of ≥ 14 days. A steady‐state plasma concentration‐time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple‐dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144–168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144–168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Inhibitory effect of Telmisartan on the blood pressure response to angiotensin II challenge

Telmisartan is a new angiotensin receptor antagonist possessing potent, selective, and insurmountable inhibitory activity specific to the angiotensin II type 1 (AT 1 ) receptor. The current study was performed to determine the inhibition of the angiotensin II pressor response by telmisartan in 48 healthy volunteers challenged with hypertension-inducing doses of i.v. angiotensin II. Subjects were challenged with this dose of angiotensin II at intervals between 0.25 and 48 h after double-blind single-dose oral administration of telmisartan 20 mg (n = 12), 40 mg (n = 12), or 80 mg (n = 12) or placebo (n = 12) in parallel groups. Diastolic and systolic blood pressure and pulse rate were recorded continuously using a servophotoplethysmograph. Urine samples were collected during the study for urinalysis. Tolerability of telmisartan, in comparison with placebo, was also monitored throughout the study. Telmisartan 20–80 mg dose dependently inhibited the increase in diastolic and systolic blood pressure induced by angiotensin II. Telmisartan 40 mg produced 80.1% maximum inhibition, and with 80 mg 89.6% maximum inhibition of diastolic blood pressure was achieved. Inhibition was apparent after 0.3–1.1 h and was still observed 48 h after administration for all telmisartan doses. The inhibitory effect of telmisartan 20, 40, and 80 mg, 48 h after dosing was significantly greater than that of placebo. A > 25% inhibition of the angiotensin II response on diastolic blood pressure was detected until 26.9, 35.4, and 40.5 h, respectively, after telmisartan 20 mg, 40 mg, and 80 mg. Anti-clockwise hysteresis was observed, indicating a delay and longer persistence of effect than to be expected from the plasma concentration–time course. The slow dissociation of telmisartan from the receptor probably contributed to this hysteresis. The incidence of adverse events was comparable in telmisartan-and placebo-treated subjects and was not dose dependent. In conclusion, telmisartan 40 mg provides rapid-onset, well-tolerated, and near-maximal inhibition of angiotensin II–induced hypertension, with maintenance of the inhibitory effect for 48 h.

ANALYSIS OF QUATERNARY AMMONIUM-COMPOUNDS AND BASIC DRUGS BASED ON ION-PAIR ADSORPTION HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY

Abstract A general approach to the ion-pair adsorption high-performance liquid chromatography of basic drugs and quaternary ammonium compounds ins decribed in which suitable counter ions such as Br − and ClO 4 − are dissolved in the eluent. The columns are packed with silica ( e.g. , Lichrosorb and LiChrosfer). The systems thus obtained showed high efficiencies and stability in which th ecapacity ratios were found to be exponentially dependent on the concentration of the counter ion. This indicates that the separation mechanism is dominated by adsorption processes. The degree of retention and the separation order can be varied by the nature and the concentration of the counter ion, the sorbent and the composition of the eluent.

Steady‐State Pharmacodynamics and Pharmacokinetics of Warfarin in the Presence and Absence of Telmisartan in Healthy Male Volunteers

The effects of multiple‐dose telmisartan on the steady‐state pharmacodynamics and pharmacokinetics of warfarin were assessed in 12 healthy young males in an open‐label, single‐period study conducted over 30 days. Subjects received loading doses of oral once‐daily warfarin on days 1 to 5, which were individually adjusted at days 6 and/or 9 to attain stable predose prothrombin time values (INRpre) of between 1.2 and 1.8 by the end of medication phase 1 (day 14). From days 15 to 24 (medication phase 2), subjects received oral once‐daily telmisartan 120 mg in addition to individualized oral doses of once‐daily warfarin. On days 25 to 31 (medication phase 3), oral once‐daily warfarin was again administered alone at individualized doses. Under steady‐state conditions, INRpre remained unchanged during medication phases 1, 2, and 3. The difference between phases 1 and 3 was −0.04 (95% confidence interval [CI]: −0.7 to 0.10) and between phases 2 and 1 was 0.03 (95% CI: −0.11 to 0.10). Mean trough plasma warfarin concentrations (Cpre) were stable during medication with warfarin alone but showed a small, although statistically significant, decrease during the combined‐medication phase. The point estimate of the ratio of phase 2/phase 1 was 0.89 (95% CI: 0.84 to 0.95). The decrease in Cpre did not result in decreased anticoagulation. This suggests that the extent of pharmacokinetic interaction between telmisartan and warfarin is limited, and since telmisartan had no effect on INRpre and the concomitant medication was well tolerated, there is no evidence for a clinically relevant interaction between telmisartan and warfarin.

Development of a laboratory robotic system for automated bioanalytical methods--I. The determination of theophylline in human plasma: a comparison between the robotized and manual method.

The quality of bioanalytical methods is often determined by the quality of sample preparation. Using a robot for sample treatment may give better results than manual sample preparation, since the robot lacks human behaviour and incidental errors that are part of it. The use of a laboratory robot has the additional advantage of giving each sample the same analytical history, resulting in better reproducibility. An automated method has been developed for the analysis of drugs in plasma using a laboratory robot. Theophylline was used as a probe drug. Sample preparation was automated with a Zymate II robot, followed by separation and quantitation on an HPLC-system. The robotic method showed a good correlation with the manual method, while sample throughput was doubled.

No Influence of Single Intravenous Doses of Omeprazole on Theophylline Elimination Kinetics

The influence of single intravenous doses of omeprazole on the pharmacokinetics of intravenously administered theophylline was studied in eight healthy male volunteers. In a partially randomized three‐period crossover design, an IV infusion of theophylline (400 mg over 30 min) was combined with IV omeprazole (either 40 mg over 2.5 min or 80 mg over 5 min) or with IV placebo (over 2.5 min). Theophylline and omeprazole plasma concentrations were measured over 24 hours after the start of the infusions and pharmacokinetic parameters were calculated. The theophylline plasma concentration‐time proxies after omeprazole coadministration were virtually identical to the corresponding profile after placebo administration. For each of the pharmacokinetic parameters of theophylline, the 90% confidence intervals of the omeprazole coadministrations were within the 80 to 120% bioequivalence range with respect to the placebo coadministration. Omeprazole plasma concentrations indicated a biexponential decline in most subjects, with a more rapid elimination after the 40‐mg than after the 80‐mg dose (P < .01). Doubling the dose caused an almost three‐fold increase of AUC resulting in a difference in clearance (P < .02), whereas the volume of distribution was similar. The results of this study indicate that the metabolism of theophylline is not affected by single intravenous doses of omeprazole. The nonlinear pharmacokinetics of omeprazole are ascribed to saturation of its main metabolizing enzyme, S‐mephenytoin hydroxylase.