Effect of Ginkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers.

PURPOSE: We assessed the human in vivo metabolic drug interaction profile of Ginkgo biloba extract EGb 761® with respect to the activities of major cytochrome P450 (CYP) enzymes. METHODS: A single-center, open-label, randomized, three-fold crossover, cocktail phenotyping design was applied. In random order, the following treatments were administered to 18 healthy men and women for 8 days each: placebo twice daily, EGb 761® 120 mg twice daily, and EGb 761® 240 mg in the morning and placebo in the evening. In the morning of day 8, administration was performed together with the orally administered phenotyping cocktail (enzyme, metric): 150 mg caffeine (CYP1A2, paraxanthine/caffeine plasma ratio 6-h postdose), 125 mg tolbutamide (CYP2C9, plasma concentration 24-h postdose), 20 mg omeprazole (CYP2C19, omeprazole/5-hydroxy omeprazole plasma ratio 3-h postdose), 30 mg dextromethorphan (CYP2D6, dextromethorphan/dextrorphan plasma ratio 3-h postdose), and 2 mg of midazolam (CYP3A, plasma concentration 6-h postdose). Formally, absence of a relevant interaction was assumed if the 90% confidence intervals (CIs) for EGb 761®/placebo ratios of the metrics were within the 0.70-1.43 range. RESULTS: EGb 761®/placebo ratios for phenotyping metrics were close to unity for all CYPs. Furthermore, respective CIs were within the specified margins for all ratios except CYP2C19 for EGb 761® 120 mg twice daily (90% CI 0.681-1.122) and for CYP2D6 for EGb 761® 240 mg once daily (90% CI 0.667-1.281). These findings were attributed to the intraindividual variability of the metrics used. All treatments were well tolerated. CONCLUSION: EGb 761® has no relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no relevant potential to cause respective metabolic drug-drug interactions.

Propiverine-induced accumulation of nuclear and cytosolic protein in F344 rat kidneys: isolation and identification of the accumulating protein.

Male and female F344 rats but not B6C3F1 mice exposed for 104 weeks to propiverine hydrochloride (1-methylpiperid-4-yl 2,2-diphenyl-2-(1-propoxy)acetate hydrochloride), used for treatment of patients with neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), presented with an accumulation of proteins in the cytosol and nuclei of renal proximal tubule epithelial cells, yet despite this, no increased renal tumor incidence was observed. In order to provide an improved interpretation of these findings and a better basis for human health risk assessment, male and female F344 rats were exposed for 16 weeks to 1000 ppm propiverine in the diet, the accumulating protein was isolated from the kidneys via cytosolic and nuclear preparations or laser-capture microdissection and analyzed using molecular weight determination and mass spectrometry. The accumulating protein was found to be d-amino acid oxidase (DAAO), an enzyme involved in amino and fatty acid metabolism. Subsequent reanalysis of kidney homogenate and nuclear samples as well as tissue sections using western blot and DAAO-immunohistochemistry, confirmed the presence and localization of DAAO in propiverine-treated male and female F344 rats. The accumulation of DAAO only in rats, and the limited similarity of rat DAAO with other species, including humans, suggests a rat-specific mechanism underlying the drug-induced renal DAAO accumulation with little relevance for patients chronically treated with propiverine.

Propiverine hydrochloride immediate and extended release: comparison of efficacy and tolerability in patients with overactive bladder.

INTRODUCTION: This study aims to compare the efficacy of propiverine hydrochloride immediate release (IR), propiverine hydrochloride extended release (ER) and placebo for the treatment of overactive bladder syndrome. The primary outcome measure is incontinence episode frequency, with secondary outcome measures including mean volume per void and quality of life as assessed on King's Health Questionnaire. MATERIAL AND METHODS: The double-blind, double-dummy, randomized study compared IR 15 mg twice daily, ER 30 mg once daily and placebo in 3 parallel groups. After a run-in period of 7 days, the patients were treated for 32 days. Nine hundred and eighty-eight patients were randomized, and 910 patients completed the protocol without major violations. RESULTS: The number of incontinence episodes/24 h decreased by 2.26 in the IR group (p < 0.001 vs. placebo), by 2.46 in the ER group (p < 0.0001 vs. placebo) and by 1.75 in the placebo group. The most frequent adverse event was dry mouth with 22.8% of the patients in the IR group, 21.7% in the ER group and 6.4% in the placebo group. The overall tolerability was rated 'very good' or 'good' by more than 80% of the investigators and patients in all 3 groups. CONCLUSIONS: Propiverine ER 30 mg once daily and propiverine IR 15 mg twice daily significantly reduce the number of incontinence episodes/24 h within a treatment period of 32 days. Both formulations are safe and well tolerated. The extended release formulation of propiverine is a suitable new option for the treatment of the overactive bladder.

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers.

The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam (2 mg orally), clearance of midazolam (1 mg i.v.), apparent clearance of tolbutamide (125 mg orally), urinary excretion of 4'-hydroxymephenytoin 0 to 8 h postdose (50 mg of mephenytoin orally), and the paraxanthine/caffeine plasma ratio 6 h postdose (150 mg of caffeine orally). These metrics were determined in 16 healthy young men at the end of 7 days of treatment with 15 mg of propiverine (test) or placebo (reference) twice daily. All phenotyping drugs were quantified by liquid chromatography-tandem mass spectrometry. Chronic propiverine treatment reduced hepatic and intestinal CYP3A4 activity slightly to 0.89-fold and 0.80-fold, respectively [90% confidence interval (CI) for test/reference ratios 0.85-0.93 and 0.72-0.89], with the combined effect resulting in a 1.46-fold increase in area under the curve of oral midazolam (90% CI 1.36-1.57). Propiverine had no relevant effect on CYP2C9, CYP2C19, and CYP1A2 (90% CI for test/reference ratios 0.93-1.00, 0.84-0.96, and 0.97-1.07, respectively). All study drugs were well tolerated. In conclusion, propiverine has a minor potential to cause drug-drug interactions.

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers.

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmacological model substance based on the "cholinergic hypothesis" of memory loss in senile dementia of the Alzheimer type. The objective of the study was to relate pharmacodynamic electroencephalogram (EEG) changes and scopolamine serum concentration using pharmacokinetic-pharmacodynamic (PK-PD) modeling techniques. This was a randomized, three-way crossover, open-label study involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (i.v.) infusion over 15 minutes or an intramuscular (i.m.) injection or a placebo. The pharmacodynamic EEG measure consists of the total power in delta, theta, alpha, and beta bands over frontal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after i.v. infusion were clearance (CL) 205 +/- 36.6 L/h, volume of distribution (Vd) 363 +/- 66.7 L, distribution half-life (t1/2 alpha) 2.9 +/- 0.67 min, and terminal half-life (t1/2 beta) 105.4 +/- 9.94 min (mean +/- SEM). Mean peak serum concentrations (Cmax) were 4.66 and 0.96 ng/ml after i.v. and i.m. administration, respectively (p < 0.05). The area under the serum concentration versus time curve (AUC) after i.m. administration (81.27 +/- 11.21 ng/ml/min) was significantly lower compared to the value after i.v. infusion (157.28 +/- 30.86 ng/ml/min) (mean +/- SEM, p < 0.05). Absolute bioavailability of scopolamine after i.m. injection was 57% +/- 0.08% (mean +/- SEM). After both i.v. and i.m. administration, scopolamine induced a decrease in EEG alpha power (7.50-11.25 Hz) over frontal, central, and occipital brain areas compared to placebo (p < 0.05). The individual concentration-EEG effect relationships determined after i.v. infusion of scopolamine were successfully characterized by a sigmoidal Emax model. The averaged values of the pharmacodynamic parameters were E0 = 0.58 microV2, Emax = 0.29 microV2, EC50 = 0.60 ng/ml, and gamma = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations of scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK-PD modeling techniques. As regards the effect on the EEG, 0.5 mg of scopolamine administered i.v. appears to be a suitable dose.

P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans.

OBJECTIVE: Increased bioavailability of the P-glycoprotein (Pgp) substrates digoxin and cyclosporin due to erythromycin has been observed in vivo. The aim of the present study was to investigate the effect of orally administered erythromycin on the oral bioavailability of the beta-blocker talinolol. Talinolol is a suitable model compound for Pgp drug-drug interaction studies due to its Pgp-related active intestinal secretion and lack of any significant metabolism. METHODS: In a randomized crossover study, the oral pharmacokinetics of talinolol (50 mg) after a concomitant single oral dose of erythromycin (2 g) or placebo were investigated in 9 healthy men. Concentrations of talinolol were measured in serum and urine by HPLC. RESULTS: The area under the curve of talinolol serum concentrations from 0 to 24 h (AUC(0-24)) and the maximum serum concentrations (Cmax) were significantly increased after administration of erythromycin compared to placebo. t(max) values were significantly reduced. The renal clearance (CLR) of talinolol was unchanged after co-administration of erythromycin and there was a small but statistically significant decrease in elimination half-life (t1/2). Serum pharmacokinetics correlate with the results derived from urine concentration measurement. One subject suffered from moderate diarrhea after erythromycin and was excluded from the analysis. CONCLUSION: We suggest that the increase in oral bioavailability of talinolol after concomitant erythromycin is caused by increased intestinal net absorption due to Pgp inhibition by erythromycin.

Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil.

OBJECTIVE: To examine the secretion of the beta1-adrenergic receptor antagonist talinolol into the small intestine during its intravenous administration and to show the relevance of the P-glycoprotein-modulating drug verapamil for this secretory transport mechanism in humans. METHODS: In six healthy volunteers the intestinal steady-state perfusion technique (triple lumen tubing system) was used for measuring the appearance of talinolol within the small intestine while the drug was infused intravenously. During four of the seven perfusions performed, the perfusion fluid was changed from a verapamil-free solution and talinolol appearance was measured while a R-verapamil-containing solution (565 micromol/L) was perfused. RESULTS: Talinolol was transported into the intestinal lumen up to a concentration gradient between lumen and blood of about 5.5:1. While perfusing the small intestine with a verapamil-free solution, the intestinal secretion rate of talinolol ranged from 1.94 to 6.62 microg/min per 30 cm length of the intestine (median values). Perfusion of a R-verapamil-containing perfusion fluid resulted in lower secretion rates (0.59 to 3.71 microg/30 cm x min), corresponding to 29% to 56% of the values obtained without verapamil supplied intraluminally. CONCLUSION: Intravenously administered talinolol is actively secreted into the human small intestine. This secretion is reduced by the intraluminal supply of the P-glycoprotein modulating drug R-verapamil. This gives further rationale for P-glycoprotein-mediated intestinal drug secretion as a cause for incomplete oral bioavailability and for drug interactions during intestinal absorption.

Unexpected effect of verapamil on oral bioavailability of the beta-blocker talinolol in humans.

PURPOSE: To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the beta1-adrenergic receptor antagonist talinolol, a substrate of P-glycoprotein. SUBJECTS AND METHODS: In a randomized, crossover placebo-controlled study, oral pharmacokinetics of talinolol (50 mg) after concomitant administration of single doses of R-verapamil (120 mg) or placebo were investigated in 9 healthy volunteers. Concentrations of talinolol, verapamil, and its main metabolite norverapamil were measured in serum with HPLC. Concentrations of talinolol were also measured in urine by HPLC. Standard pharmacokinetic parameters were calculated with noncompartmental procedures. RESULTS: The area under the concentration-time curve for talinolol from 0 to 24 hours was significantly decreased after R-verapamil versus placebo (721+/-231 ng x h x mL(-1) versus 945+/-188 ng x h x mL(-1); P < .01). Maximum serum concentration of talinolol was reached significantly earlier after R-verapamil compared with placebo (P < .05). Coadministration of R-verapamil did not affect the renal clearance or half-life of talinolol. Serum pharmacokinetics are paralleled by the results derived from urine concentrations of talinolol. CONCLUSION: This is the first study to show a decreased oral bioavailability of a P-glycoprotein substrate (talinolol) in humans as a result of coadministration of verapamil. This effect is assumed to be caused by changes of the intestinal net absorption of talinolol because its renal clearance remains unaffected by administration of R-verapamil. This unexpected effect of R-verapamil is most likely dose dependent as a result of an interplay between intestinal P-glycoprotein and gut metabolism.

Determination of drugs in biological fluids by high-performance liquid chromatography with on-line sample processing.

An automated two column HPLC system with the new packing material LiChrospher RP-18 ADS (alkyl-diol-silica) was tested for the determination of several drugs and metabolites (talinolol, celiprolol, metoprolol, oxprenolol, triamterene, trimethoprim, tiracizine, articaine, detajmium, ajmaline, lamotrigine) in various biological fluids (serum, urine, intestinal aspirates, supernatants of cell cultures and supernatants after protein denaturation). The method allows the direct injection of biological fluids into a reversed-phase HPLC system and on-line clean-up and sample enrichment by a column-switching technique. Precision, accuracy and sensitivity were similar to conventional assays as described in the literature. With this new method it was possible to measure drug concentrations in various biological fluids without changing the sample preparation procedure. In some cases an additional sample preparation like protein denaturation or solid-phase extraction was advantageous to enhance the sensitivity of the method and the life-time of the ADS column.

Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype.

BACKGROUND: Codeine is widely used as an analgesic and antitussive drug. The analgesic effect of codeine is mediated by its metabolite morphine, which is formed by the polymorphically expressed enzyme CYP2D6; therefore poor metabolizers have no analgesia after administration of codeine. Like other opiates, codeine causes a delay of gastric emptying and spastic constipation. It is not yet known whether the effect on gastrointestinal motility is mediated by codeine or its metabolite morphine. METHODS: To test the hypothesis that the metabolite morphine is responsible for the effects of codeine on gastrointestinal motility, a randomized, double-blind, two-way crossover study was performed. The orocecal transit time was studied in five extensive and five poor metabolizers of sparteine with the sulfasalazine-sulfapyridine method, assuming that no effects are observed in poor metabolizers because negligible amounts of morphine are formed. RESULTS: No differences of orocecal transit times were observed between extensive metabolizers and poor metabolizers after oral placebo administration. However, after oral codeine administration orocecal transit time was significantly prolonged in extensive metabolizer but not poor metabolizer subjects. All pharmacokinetic parameters of codeine showed no differences between extensive metabolizers and poor metabolizers. The pharmacokinetic parameters (mean +/- SD) of the metabolite morphine were significantly different between extensive metabolizer and poor metabolizer subjects (peak serum concentration, 13.9 +/- 10.5 versus 0.68 +/- 0.15 pmol/ml; area under the serum concentration-time curve, 27.8 +/- 16.0 versus 1.9 +/- 0.7 hr.pmol/ml; total amount of morphine excreted in urine, 0.160 +/- 0.036 versus 0.015 +/- 0.007 mumol). CONCLUSIONS: Because the orocecal transit time prolongation after codeine administration was observed only in extensive metabolizers, the effect of codeine on gastrointestinal motility, like the analgesia, is mediated by its metabolite morphine.

Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans.

OBJECTIVE: To examine the relevance of site-dependent small intestinal absorption for incomplete intestinal absorption of the poorly metabolized beta 1-adrenergic receptor antagonist talinolol. METHODS: The intestinal steady-state perfusion technique (triple lumen tubing system with a 30 cm test segment) for intraluminal measurements was combined with simultaneous determination of talinolol serum concentrations. Dissolved talinolol was perfused over 160 minutes into different parts of the small intestine. The middle of the test segment was located between 25 and 235 cm beyond the teeth. Each of the six healthy subjects was studied twice with a proximal and a more distal site of perfusion to allow for comparisons within an individual subject. RESULTS: The area under the curve for serum concentrations from 0 to 480 minutes [AUC(0-480 min)] and the maximum serum concentration after distal perfusions corresponded to only 15% to 73% and 7% to 90% of the proximal values, respectively. AUC decreased with increasing distance from the teeth. The mean amount of talinolol absorbed from the test segment per unit time (intestinal transport rate) corresponds to only one-tenth of the amount of drug offered to the test segment (perfusion rate). There was a direct correlation between the perfusion rate of talinolol and its transport rate for both regions and in all subjects investigated. However, to achieve the same transport rate in the distal region a higher perfusion rate is required, compared to the proximal small intestine. At perfusion rates lower than 600 micrograms/min, net secretion of talinolol into the intestinal lumen occurred against a steep concentration gradient blood: lumen of about 1:4200. CONCLUSION: Talinolol oral bioavailability of 55% is due to a low absorption rate and a decrease of absorption capabilities along the small intestine. Net absorption of talinolol is reduced by the involvement of active intestinal secretion.

Disposition and bioavailability of the beta 1-adrenoceptor antagonist talinolol in man.

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective beta 1-adrenoceptor antagonist talinolol (Cordanum--Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (Cmax) of 631 +/- 95 ng mL-1 (mean +/- SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC0-infinity) was 1433 +/- 153 ng h mL-1. The following parameters were estimated: terminal elimination half life (t 1/2), 10.6 +/- 3.3 h; mean residence time, 11.6 +/- 3.1 h; volume of distribution, 3.3 +/- 0.5 L kg-1; and total body clearance, 4.9 +/- 0.6 mL min-1 kg-1. Within 36 h 52.8 +/- 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 +/- 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a Cmax of 168 +/- 67 ng mL-1 was reached after 3.2 +/- 0.8 h. The AUC0-infinity was 1321 +/- 382 ng h mL-1. The t 1/2 was 11.9 +/- 2.4 h. 28.1 +/- 6.8% of the dose or 55.0 +/- 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 +/- 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 +/- 15% (95% confidence interval, 36-69%).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of the antiarrhythmic agent tiracizine: steady state kinetics in comparison with single-dose kinetics.

Serum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine-induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1, Cmax,ss = 391.8 ng mL-1 against Cmax,sd = 132.8 ng mL-1; M2, Cmax,ss = 143.2 ng mL-1 against Cmax,sd = 25.8 ng mL-1). However, significant increases of AUC (AUC tau = 261.9 ng h mL-1 against AUC0-infinity,sd = 182.9 ng h mL-1), Cmax (Cmax,ss = 75.9 ng mL-1 against Cmax,sd = 56.9 ng mL-1) and t 1/2 beta (t 1/2 beta,ss = 4.0 h against t 1/2 beta,sd = 2.4 h) of the parent compound indicate non-linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non-renal tiracizine clearance with repeated dosing led to the assumption that non-linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at the tmax of the parent compound, whereas there was no change in any ECG parameter after a single-dose administration of 50 mg tiracizine.

Day-night variations in the renal excretion of the antiarrhythmic agent tiracizine and its metabolites.

Daytime and nighttime urinary recovery as well as morning and evening trough serum levels of the antiarrhythmic agent tiracizine and three of its metabolites (M1, M2, and M3) were assessed during a 7-day multiple-dose study period (50 mg tiracizine twice daily) in eight healthy volunteers. A significantly lower mean steady-state urinary recovery was observed during the daytime as compared with during the nighttime (Ae (tot tau d)=42.0 +/- 15.7% vs. Ae (tot tau n)=51.2 +/- 19.6%). This difference is mainly due to a substantial increase of M1 and a smaller increase of M2 urinary recovery by night. Results of additional in vitro investigations showed the ratio of the nonionic/ionic forms of M1 and M2 to be highly dependent on pH in the range of pH 5-pH 7. Therefore, the observed day-night variations might be attributed to alterations of ionization, i.e., nonionic tubular reabsorption of the metabolites due to circadian differences in urinary pH. Trough serum levels of M1 and M2 tended to be higher at 7 P.M. as compared with 7 A.M. Due to the narrow therapeutic index of class I antiarrhythmics, the present results indicate the need for further investigations concerning the effect of urinary pH on the pharmacokinetics of tiracizine and its metabolites.

[Relative bioavailability of the antiarrhythmia agent, tiracizine and its metabolites]. / Relative Bioverfügbarkeit des Antiarrhythmikums Tiracizin und seiner drei Metabolite.

Relative bioavailability of a 100 mg tablet formulation of the antiarrhythmic agent tiracizine (CAS 78816-67-8) compared to a 50 mg formulation was assessed in a simple cross over study after single administration of a 100 mg dose to 12 healthy volunteers. Tiracizine and three of its metabolites (M1, M2 and M3) were measured in serum and urine by high pressure liquid chromatography. AUC (means after administration of the test preparation and 95% nonparametric confidence interval for the ratio test preparation/reference preparation) were 391.5 ng.h/ml and 0.87-1.11 for tiracizine, 5184.5 ng.h/ml and 0.94-1.26 for M1, and 1319.9 ng.h/ml and 0.88-1.16 for M2. Mean maximum serum concentrations after the test preparation and corresponding 95% confidence interval were 111.2 ng/ml and 0.86-1.20 for tiracizine, 301.2 ng/ml and 0.98-1.22 for M1, 54.6 ng/ml and 0.86-1.17 for M2, and 35.2 ng/ml and 0.82-1.17 for M3.tmax did not differ after the two preparations for tiracizine, M2 and M3, but was significant lower for M1 after administration of the test preparation (2.2 +/- 0.7 vs 3.0 +/- 1.2 h). Total urinary recovery (sum of parent compound and metabolite recovery) up to 32 h after intake of the test preparation was 31.2% of the administered dose. The corresponding 95% confidence interval was 0.84-1.08. Statistical evaluation of all parameters revealed bioequivalence between the two preparations if a single dose of 100 mg is administered.

[The bioequivalence of metoclopramide in two tablet formulations]. / Untersuchung zur Bioäquivalenz von Metoclopramid in zwei Tablettenformulierungen.

An investigation on the bioavailability of a tablet with 10 mg metoclopramide-HCl (CAS 363-62-5) Cerucal was performed in a two-way cross-over study with 12 volunteers. Metoclopramide was determined in serum by HPLC. The relative bioavailability (mean and nonparametric 95% confidence interval) with respect to a reference preparation was 0.95 (95% CI 0.88-1.02) for AUC and 0.92 (95% CI 0.79-1.07) for Cmax. A positive decision for bioequivalence was derived from the usual confidence intervals for both parameters. The tmax-values did not differ significantly. Statistical evaluation of all parameters revealed bioequivalence between the two preparations.

Griseofulvin absorption from different sites in the human small intestine.

The site-dependent small-intestinal absorption pattern of griseofulvin was investigated in man. Griseofulvin was chosen as a model substance having extremely low water solubility and moderate lipid solubility. A conventional steady-state perfusion technique (triple-lumen tubing system with a 20 cm test segment) was applied. Dissolved griseofulvin (10.0 mg L-1) was perfused (10 mL min-1) during 160 min into different parts of the small intestine with the middle of the test segment between 85 cm and 270 cm beyond the teeth. Each of the ten healthy volunteers was examined twice with the test segment localized in different regions to allow for intraindividual comparisons. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in the two intestinal parts (proximal, 15.0 +/- 5.9 micrograms (20 cm min)-1; distal, 16.2 +/- 4.3 micrograms (20 cm min)-1; mean +/- SD). Absorption rate was strongly correlated to the amount of griseofulvin offered to the test segment per unit time. Extrapolating these findings it follows that an amount of griseofulvin, once dissolved, would be absorbed completely (> 99%) along 100 cm of the small intestine. A significant, positive correlation between the rate of transmucosal fluid transport and the absorption rate of griseofulvin was observed in the distal parts investigated.

Dose dependent tiracizine disposition in healthy volunteers: serum and urine kinetics and dose related ECG-changes.

The pharmacokinetics of tiracizine, a new class I antiarrhythmic agent, and 3 of its metabolites were assessed in serum and urine of 8 healthy extensive metabolisers after single oral administration of 50, 100, and 200 mg tiracizine hydrochloride. Additionally, tiracizine induced ECG-changes were compared between the different doses. With increasing doses enhancement of AUC and Cmax of tiracizine and its metabolites revealed a slight deviation from linearity indicated by exceeding the upper limits of the 95% nonparametric confidence interval set by 0.8-1.2 for the ratio (dose corrected parameters after the 100 and 200 mg dose, respectively)/(parameters after 50 mg). The increase of the dose corrected parameters after the 200 mg dose was about 1.3-fold compared with the 50 mg parameters for the parent compound as well as its metabolites. The significant decrease of the renal clearance of all 4 substances with increasing doses indicates that saturable tubular secretion mainly accounts for non-linearity. Due to the occurrence of non-linear (tubular secretion) as well as linear (glomerular filtration, hepatic metabolism) elimination in parallel, however, it is concluded that saturable tubular secretion is of minor importance at higher doses and should not be overestimated. However, there was some evidence for saturable hepatic tiracizine metabolism in 4 of the 8 participants. Therefore, a fall of apparent intrinsic clearance has also to be taken into consideration, especially at higher doses. PQ- and QRS-intervals were prolonged in a dose dependent manner and culminated at 1 h after drug intake. QTc-time, however, remained unchanged. A log-linear relationship between serum concentrations of the parent compound and PQ- as well as QRS-time is suspected for serum levels about 80 ng/ml, but has to be confirmed by individual pharmacokinetic-pharmacodynamic modelling. PQ- and QRS-intervals might be suitable for tiracizine therapeutic monitoring.

Elucidation of the structure of talinolol metabolites in man. Determination of talinolol and hydroxylated talinolol metabolites in urine and analysis of talinolol in serum.

The objective of this study was to determine the structure of talinolol metabolites formed and the amounts excreted in urine. Talinolol metabolites in urine were identified by comparing their HPLC retention times and their GC-MS profile with those of previously characterized reference compounds. The metabolites were quantified by HPLC with a normal-phase silica column, a single chloroform extraction and UV detection. Less than 1% of an administered dose was found in urine as hydroxylated talinolol. Other metabolites could be excluded. A sensitive method to determine talinolol in serum and a simple method for analysis of talinolol in urine are described. These methods were found to be precise and accurate for the measurement of talinolol in samples obtained from patients during chronic talinolol treatment as well as from healthy volunteers after a single dose of talinolol.