Effects of advanced age and renal dysfunction on the single- and repeated-dose pharmacokinetics of modified-release flupirtine.

BACKGROUND: Flupirtine is a nonopioid, central analgesic without antipyretic or antiphlogistic properties. Flupirtine-MR is an oral modified-release formulation with a 100 mg fast-input and a 300 mg portion with slow protracted release. METHODS: Single- (D01) and repeated-dose (D03-D09) pharmacokinetics of 400 mg flupirtine-MR were investigated in patients with severe renal dysfunction (REN: N: 12; 21 50 years of age; creatinine clearance (CLCr)≤30 mL/min per 1.73 m2 body surface area (BSA)) and healthy older subjects (EN1: N: 8; 60-69 years; CLCr≥80 mL/min and EN2: N: 8; ≥70 years, CLCr≥60 mL/min) vs. young healthy control subjects (YN: N: 12; 21-40 years; CLCr≥90 mL/min). RESULTS: Renal dysfunction led to a relatively small average increase in systemic exposure to flupirtine: on D09, the REN : YN-ratios were 1.37 (95% confidence interval (CI): 1.03-1.82), 1.21 (CI: 1.01-1.45), and 1.34 (CI: 1.09-1.64) for Css,0, Css,max, and Css,av, respectively. A similar increase in exposure was observed in older subjects: the respective EN1:YN-ratios were 1.30 (CI: 0.95-1.79), 1.23 (CI: 1.01-1.49), and 1.23 (CI: 0.98-1.54); the EN2:YN-ratios were 1.50 (CI: 1.10-2.04), 1.16 (CI: 0.85-1.41), and 1.41 (CI: 1.12-1.79), respectively. Neither age nor renal function was a predominant factor of pharmacokinetic variability. Single and repeated doses of flupirtine-MR were very well tolerated. CONCLUSIONS: The average renal and age effects were small, but the use of a lower starting dose (1/2 tablet) is recommended since some of these subjects might have relatively high exposure levels.

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1.

AIMS: The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. METHODS: Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). RESULTS: Flupirtine IR was rapidly but incompletely absorbed (∼ 72%). Repeated administration of flupirtine MR showed lower bioavailability (∼ 60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2. CONCLUSIONS: Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1.

Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study.

OBJECTIVE: To demonstrate non-inferior/superior efficacy of flupirtine modified release (MR) compared with tramadol/placebo for the management of moderate to severe chronic low back pain (LBP). RESEARCH DESIGN: Randomized, double-blind, active-/placebo-controlled double-dummy multicenter study, performed in 31 German study centers. LBP patients (n = 363) with moderate pain intensity were randomized 1:1:1 to receive flupirtine MR 400 mg, tramadol extended release (ER) 200 mg, or matching placebo (each given OD in the evening) over 4 weeks. CLINICAL TRIAL REGISTRATION: EudraCT 2009-013268-38. MAIN OUTCOME MEASURES: Primary endpoint was change from baseline in the LBP intensity index (LBPIX; 11-point NRS) at week 4; last observation carried forward was used to impute missing scores. RESULTS: Least square (LS) mean ± SD LBPIX changes from baseline at week 4 were clinically significant for all three treatment groups of the intent-to-treat (ITT) and the per-protocol (PP) population (n = 326/276): placebo (n = 110/96): -1.81 ± 1.65/-1.77 ± 1.59; flupirtine MR (n = 109/95): -2.23 ± 1.73/-2.28 ± 1.68; and tramadol ER (n = 107/85): -1.92 ± 1.84/2.03 ± 1.83 (p < 0.001 for each). ITT/PP treatment effects for flupirtine MR were non-inferior when compared with tramadol ER and superior when compared with placebo (p = 0.003/0.033). Significantly more ITT patients treated with flupirtine MR (59.6/37.6 showed a ≥30/50% LBPIX relief in comparison to placebo (46.4/24.6%; p vs. flupirtine MR: 0.049/0.037). Treatment contrasts for tramadol failed to reach significance vs. placebo. Within the safety population (n = 355), flupirtine MR (n = 119) was associated with a significantly lower incidence of treatment emergent AEs (TEAEs; 21.0%) and TEAE-related study discontinuations (3.4%) than tramadol ER (n = 116; 34.5/12.0%; p = 0.039/0.017) and exhibited an overall safety/tolerability profile non-inferior to placebo (n = 120; 15.8/3.3%; p = ns for each). Major limitations of this study were the short treatment duration, the comparison of different drug classes and the lack of a titration phase. CONCLUSIONS: The analgesic efficacy of flupirtine MR 400 mg OD was comparable to that of tramadol ER 200 mg OD and superior to that of placebo.

In vivo probes of drug transport: commonly used probe drugs to assess function of intestinal P-glycoprotein (ABCB1) in humans.

Intestinal P-glycoprotein (P-gp, ABCB1) may significantly influence drug absorption and elimination. Its expression and function is highly variable, regio-selective and influenced by genetic polymorphisms, drug interactions and intestinal diseases. An in vivo probe drug for intestinal P-gp should a registered, safe and well tolerated nonmetabolized selective substrate with low protein binding for which P-gp is rate-limiting during absorption. Other P-gp dependent processes should be of minor influence. The mechanism(s) and kinetics of intestinal uptake must be identified and quantified. Moreover, the release properties of the dosage form should be known. So far, the cardiac glycoside digoxin and the ß1-selective blocker talinolol have been used in mechanistic clinical studies, because they meet most of these criteria. Digoxin and talinolol are suitable in vivo probe drugs for intestinal P-gp under the precondition, that they are used as tools in carefully designed pharmacokinetic studies with adequate biometrically planning of the sample size and that several limitations are considered in interpreting and discussion of the study results.

Investigation of the in vitro metabolism of the analgesic flupirtine.

The in vitro metabolism of flupirtine, ethyl-N-[2-amino-6-(4-fluorophenylmethyl-amino)pyridine-3-yl]carbamate, a centrally acting analgesic with muscle tone-reducing activity, was studied. Two flupirtine metabolites were already known: the N-acetylated analog D13223 and 4-fluorohippuric acid. The structure of flupirtine suggested that redox chemistry may play a role in metabolism, and cyclic voltammetry studies showed that the drug undergoes facile and irreversible redox reactions. Thus, oxidative metabolism was investigated first. With CYP3A1-induced rat liver microsomes an 18% turnover of flupirtine and a 20 to 25% turnover of D13223 took place over 30 min, but less than 5% turnover of flupirtine was observed with all human liver microsomal preparations tested, evidence that cytochrome P450 does not contribute appreciably to the metabolism in humans. Likewise, no involvement of human monoamine oxidase (isoforms A and B) was found for either flupirtine or D13223. In contrast, flupirtine was an excellent substrate for both human myeloperoxidase and horse radish peroxidase (HRP). These enzymes produced detectable amounts of oxidation products. Incubations of flupirtine with HRP produced an oxidation product that could be trapped with glutathione, the resulting glutathione conjugate was characterized by mass spectrometry and NMR. Metabolism of D13223 by both peroxidases was also observed but to a much lesser extent. Porcine liver esterases cleave the carbamate group of flupirtine, and both human N-acetyltransferases 1 and 2 acetylated the hydrolysis product, presumably descarboethoxyflupirtine, with nearly equal efficiencies to yield D13223. Incubations of human liver microsomes with flupirtine or the metabolite D13223 together with UDP-glucuronic acid gave two isomeric N-glucuronides in both cases.

Determination of talinolol in human plasma by high performance liquid chromatography-electrospray ionization mass spectrometry: application to pharmacokinetic study.

A rapid and sensitive method for determination and screening in human plasma of talinolol is described using propranolol as the internal standard. The analytes in plasma were extracted by liquid-liquid extraction using methyl t-butyl ether. After removed and dried the upper organic phase, the extracts were reconstituted with a fixed volume of buffer of ammonium acetate and acetonitrile (60:40, v/v). The extracts were analyzed by a HPLC coupled to electrospray ionization mass spectrometry (HPLC-MS/ESI). The HPLC separation of the analytes was performed on a Phenomenex C18 (250 mmx4.6 mm, 5 microm, USA) column, with a flow rate of 0.85 mL/min. The complete elution was obtained within 5.5 min. The calibration curve was linear in the 1.0-400.0 ng/mL range for talinolol, with a coefficient of determination of 0.9996. The average extraction recovery was above 83%. The methodology recovery was between 101% and 102%. The limit of detection (LOD) was 0.3 ng/mL for talinolol. The intraday and inter-day coefficients of variation were less than 6%. This HPLC-MS/ESI procedure was used to assess the pharmacokinetics of talinolol. A single oral 50 mg dose of talinolol tablet was administered to 12 healthy Chinese volunteers, the main pharmacokinetic data are as follows: Cmax was 147.8+/-63.8 ng/mL; tmax was 2.0+/-0.7 h; t1/2 was 12.0+/-2.6 h. The method is accurate, sensitive and simple for the pharmacokinetic study of talinolol.

Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers.

OBJECTIVE: To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the beta1 adrenoceptor blocker talinolol. METHODS: The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant administration of curcumin (300 mg day(-1) for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS: (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered to be significant at p < 0.05 (two-sided test). RESULTS: The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity (AUC(0-infinity)) of talinolol from 1860.0 +/- 377.9 to 1246.0 +/- 328.2 ng x h mL(-1), the highest observed concentration values (C(max)) were significantly decreased from 147.8 +/- 63.8 to 106.4 +/- 39.9 ng mL(-1), and the CL/F was increased from 27.9 +/- 5.5 to 43.1 +/- 13.4 L x h(-1) (p < 0.05). There was no significant difference in sampling time for C(max) (t(max)) and elimination half-life (t(1/2)) values between the two periods (p > 0.05). The interindividual variability in AUC(0-60) and C(max) of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC(0-60) and C(max) was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively. CONCLUSION: We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration, or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues.

Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms.

AIMS: To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the beta(1)-selective blocker talinolol, a substrate of these transporter proteins. METHODS: The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0-27.0 kg m(-2)) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady-state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real-time reverse transcriptase-polymerase chain reaction (TaqMan. RESULTS: Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC(0-infinity) (r = 0.627, P = 0.039) and C(max) (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half-life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild-type SLCO1B1*1a/*1a genotype (12.2 +/- 1.6 h vs. 14.5 +/- 1.4 h, P = 0.01). CONCLUSIONS: Simvastatin does not influence the intestinal expression of P-gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co-administration to healthy subjects.

Variability of intestinal expression of P-glycoprotein in healthy volunteers as described by absorption of talinolol from four bioequivalent tablets.

The beta(1)-selective blocker talinolol is incompletely absorbed in man from an "absorption window" in the upper small intestine which is under control of P-glycoprotein. The following single dose, four-period, changeover study with 7 days washout in 36 healthy subjects (21 females, age 20-33 years) was designed to confirm bioequivalence of four marketed tablet formulations of talinolol with identical in vitro liberation and to deduce from the intrasubject and intersubject variability of talinolol pharmacokinetics on the variability of intestinal P-gp function. All point estimates of the primary criteria AUC(0-infinity) and C(max) for the comparison of the galenic forms were within 0.9-1.10. The 90% confidence intervals were entirely within the standard ranges of bioequivalence (0.80-1.25 for AUC(0-infinity), 0.70-1.43 for C(max)). The intra- and intersubject coefficients of variation for AUC(0-infinity) were 14.0% and 20.4-29.5%, respectively. In conclusion, the four talinolol tablets are bioequivalent in extent and rate of absorption. The low intrasubject variability of the AUC(0-infinity) after weekly administration of the tablets refers to a small intrasubject variability of the "absorption window" and elimination of talinolol that most likely depends on the expression of P-gp in the small intestine.

Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition.

OBJECTIVE: Thyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P-glycoprotein, we hypothesized that thyroid hormones may regulate P-glycoprotein and influence disposition of P-glycoprotein substrates. METHODS: Duodenal expression of P-glycoprotein measured by reverse transcriptase-polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22-29 years; body weight, 59-89 kg) before and after coadministration with levothyroxine (200 microg orally for 17 days), which resulted in suppression of thyroid-stimulating hormone. The pharmacokinetics of the P-glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration. RESULTS: Duodenal MDR1 mRNA expression and immunoreactive P-glycoprotein were increased 1.4-fold (not significant; P =.078) and 3.8-fold (P <.01), respectively, after administration of levothyroxine. The changes in P-glycoprotein expression were associated with minor alterations in talinolol half-life after both oral and intravenous administration. CONCLUSIONS: Expression of intestinal P-glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.

[Application of quantifying scoring systems for the determination of changes in the mucosa of the upper gastrointestinal tract. A comparative study of a diclofenac effervescent tablet with conventional diclofenac preparations and acetylsalicylic acid after repeated administration]. / Einsatz quantifizierender Scoring-Systeme zur Ermittlung von Schleimhautveränderungen des oberen Gastrointestinaltraktes. Vergleichende Untersuchung einer Diclofenac-Brausetablette, konventioneller Diclofenac-Zubereitungen sowie von Acetylsalicylsäure nach wiederholter Anwendung.

UNLABELLED: Application of Quantifying Scoring Systems for the Determination of Changes of the Mucosa of the Upper Gastrointestinal Tract/A comparative study of a diclofenac effervescent tablet with conventional diclofenac preparations and acetylsalicylic acid after repeated administration. BACKGROUND AND AIM: A new diclofenac effervescent tablet (DIC-BT) was developed in order to circumvent the high variable delay in delivery of the drug in enteric coated tablets of diclofenac (CAS 15307-86-5). The gastrointestinal side effects of the effervescent tablet were investigated in comparison to two other galenic principles of DIC preparations (DIC entero coated dragees = DIC-mrD) and dispersible tablets (DIC-DispT) and to acetylic salicylic acid (ASA (CAS 50-78-2). For the assessment of gastrointestinal side effects, two score systems were used simultaneously. The Lanza-scores were compared with our HEU-criteria system (Haemorrhage, Erosion, Ulceration) to find out if the pattern and the localisation of the lesions differ between the drugs tested. METHODS: In a single-blind, randomised, controlled, parallel study design healthy volunteers (27 females, 33 males; mean age 26.9 years, mean b.w. 72.5 kg, Helicobacter pylori antibody negative) were treated by 150 mg/d DIC or 1500 mg ASA (as positive control group) for 7 days. DIC-BT (n = 20 subjects), DIC enteric coated dragees (DIC-mrD) (n = 20), DIC-Dispers tablets (DIC-DispT) (n = 10) and ASA (n = 10) were administered t.i.d. The effects were investigated by videoendoscopy with chromoscopy before and after treatment. Mucosa lesions were assessed according to the Lanza-scores and HEU-criteria system. The results were calculated as pre-post comparison and assessed as paired test between treatment groups. RESULTS: DIC preparations caused mostly erosions and scarcely haemorrhages, but different from ASA only few combined lesions of haemorrhages and lesions in Corpus ventriculi and Bulbus duodeni. The number of mucosal lesions was different with regard to the region (Antrum ventriculi > Corpus ventriculi > Bulbus duodeni). The spreading with Helicobacter pylori (histological assessment at the end of study) varied between 20% and 50% (7/20 subjects in DIC-BT and DIC-msrD, respectively, 5/10 in DIC-dispT group, 2/10 subjects in the ASA group). Based on the HEU-criteria, erosions were seen in 9/20 subjects in DIC-BT, 10/20 subjects in DIC-mrD, 4/10 in DIC-DispT, and 3/10 subjects in ASA group, respectively, the combination of haemorrhages and erosions is seen in 2/20 subjects in DIC-BT, 6/20 in DIC-mrD, 4/10 subjects in DIC-DispT, and in 7/10 subjects in the ASA group, respectively. The difference is significantly between DIC-BT and ASA (p < 0.05) to the sum of all lesions in stomach. Based on Lanza-scores (score values > 2), (a) erosions were seen in 7/20 subjects in DIC-BT, 15/20 subjects in DIC-mrD, 7/10 in DIC-DispT, and 9/10 subjects in ASA group; (b) haemorrhages were seen in 0/20 subjects in DIC-BT, 5/20 subjects in DIC-mrD, 2/10 in DIC-DispT, and 4/10 subjects in ASA group, (c) combined type in 3/20 subjects in DIC-BT, 8/20 subjects in DIC-mrD, 5/10 in DIC-DispT, and 8/10 subjects in ASA group, respectively. Independent of the scoring systems, the difference was significant between DIC-BT and DIC-mrD, as well as between all DIC preparations and ASA. At the end of the study Helicobacter pylori infections were observed by biopsy in 20-50% of volunteers (DIC-BT and DIC-mrD in 7/20 subjects, each, and DIC-DispT in 5/10, and ASA in 2/10 subjects, respectively) and between Dic-BT and ASA (p < 0.05) for all categories. CONCLUSION: Mucosal lesions induced by DIC-BT were significantly less than by DIC-mrD and DIC-DispT. The effect was confirmed by both scoring systems, i.e. Lanza scores and HEU-criteria system. Using the HEU-criteria the pattern and the localization of the lesions could be characterized. There were remarkable differences between the effects of DIC and ASA. The assessment of gastrointestinal side effects using the HEU-criteria was superior to Lanza-scores because there was no bias according to the type of lesion and the type of drug.

[Registration of drug-associated lesions of the mucosa of the upper gastrointestinal tract. The problem of characterizing the health status of healthy subjects]. / Erfassung von Arzneimittel-assoziierten Schädigungen an der Schleimhaut des oberen Intestinaltraktes. Zum Problem einer Charakterisierung des Gesundheitsstatus gesunder Probanden.

BACKGROUND AND AIM: Investigations with regard to toxic effects of drugs on the upper gastrointestinal tract depend on healthy volunteers with normal mucosal conditions. Because of the high prevalence of Helicobacter pylori infection it is mandatory to exclude infected volunteers without abdominal history as early as possible. This study was to compare the power of non-invasive and invasive tests in the selection of volunteers without gastric disease. METHOD: 85 healthy volunteers (age 18-35 years) without abdominal history underwent both gastroduodenoscopy and specific tests for Helicobacter pylori infection (IgA- and IgG-antibodies, ureasetest, culture, HE-staining). In the case of pathological findings, the biopsies were performed without including the subjects into the study with a non-steroidal anti-inflammatory drug (NSAIDs) (Diclofenac, CAS 15307-86-5). The invasive tests of volunteers, who were selected, were performed at the end of drug period, because biopsies would influence the outcome of a 7-day treatment with diclofenac RESULT: Initially 25/85 volunteers without any history of abdominal disease must be excluded. In 15 subjects there were abnormal concentrations of IgG- and/or IgA- antibodies against Helicobacter pylori. Endoscopically in 10 persons severe lesions were found (6 ulcer and/or erosions and/or reflux disease). In 18 subjects histologically the Helicobacter pylori infection was confirmed. At the end of the treatment period in 17/60 volunteers a positive Helicobacter pylori staining was found. Comparing five Helicobacter pylori tests there were no significant correlations between non-invasive and invasive procedures. CONCLUSION: The endoscopic investigation (gastroduodenoscopy) was the only valid method to differentiate between healthy volunteers and subjects with mucosal lesions. With regard to Helicobacter pylori infection neither the non-invasive nor the invasive tests were significantly correlated. Therefore, in investigations on the toxic effect of drugs the infection rate must be determined after treatment to prove the homogeneity of and between the groups. Most important is a subtile endoscopic technique which depends on high resolution video-endoscopes, chromoscopy as well as inter- and intra-observer variation procedures.

Stereoselective disposition of talinolol in man.

The disposition of the beta-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) before and after comedication of rifampicin (600 mg per day for 9 days) in eight male healthy volunteers (age 22-26 years, body weight 67-84 kg) with respect to differences in the kinetic profiles of the two enantiomers S(-) talinolol and R(+) talinolol. Additionally, the metabolism of talinolol in human liver microsomes was examined. After oral administration, S(-) talinolol was slightly less absorbed and faster eliminated than R(+) talinolol. The absolute bioavailabilty of the R(+) enantiomer of talinolol was slightly but significantly higher than of its S(-) enantiomer. Coadministration of rifampicin further intensified this difference in the disposition of R(+) and S(-) talinolol (p < 0.05). Formation of 4-trans hydroxytalinolol was the major metabolic pathway in human liver microsomes. All Cl(int) values of S(-) were higher than of R(+) talinolol; 0.1 microM ketoconazole inhibited the formation of all metabolites. In conclusion, the stereoselectivity of talinolol disposition is of minor importance, and most likely caused by presystemic biotransformation via CYP3A4. The less active R(+) talinolol might be suitable for phenotyping P-glycoprotein expression in man.