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Wilhelm Kirch - One of the best experts on this subject based on the ideXlab platform.
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Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of Talinolol.
Clinical pharmacology and therapeutics, 2007Co-Authors: Ute I. Schwarz, Reinhard Oertel, Stephan Miehlke, Eberhard Kuhlisch, Richard B. Kim, H. Hanso, Hartmut Glaeser, Monika Hitzl, George K. Dresser, Wilhelm KirchAbstract:St John's wort (SJW) is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. Our study evaluated the effects of long-term SJW administration on oral and intravenous pharmacokinetics of the nonmetabolized in vivo probe of P-glycoprotein, Talinolol, in relation to intestinal P-glycoprotein expression. In a controlled, randomized study (N=9), the pharmacokinetics of oral (50 mg) and intravenous Talinolol (30 mg) was determined before and after 12 days SJW (900 mg daily, Jarsin 300®). Duodenal biopsies were taken and MDR1 genotypes assessed. SJW reduced the oral Talinolol bioavailability by 25% (P=0.049) compared with water control. A 93% increase in oral clearance (P=0.177) and a 31% reduction in area under the serum concentration time curve (AUC; P=0.030) were observed. Renal and nonrenal clearance (CLNR), elimination half-life, peak serum drug concentration (Cmax), and time to reach Cmax were not significantly altered. After intravenous Talinolol, SJW affected only CLNR (35% increase compared with water, P=0.006). SJW increased MDR1 messenger ribonucleic acid (mRNA) as well as P-glycoprotein levels in the duodenal mucosa. Subjects with the combined MDR1 genotype comprising 1236C>T, 2677G>T/A, and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and displayed an attenuated inductive response to SJW as assessed by Talinolol disposition. Long-term SJW decreased Talinolol AUC with a corresponding increase in intestinal MDR1 expression, suggesting that SJW has a major inductive effect on intestinal P-glycoprotein. Interestingly, the magnitude of induction appeared to be affected by MDR1 genotype. Clinical Pharmacology & Therapeutics (2007) 81, 669–678. doi:10.1038/sj.clpt.6100191; published online 28 March 2007
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Grapefruit juice ingestion significantly reduces Talinolol bioavailability.
Clinical pharmacology and therapeutics, 2005Co-Authors: Ute I. Schwarz, Reinhard Oertel, Diana Seemann, Stephan Miehlke, Eberhard Kuhlisch, Martin F. Fromm, Richard B. Kim, David G. Bailey, Wilhelm KirchAbstract:Objectives Our objectives were to evaluate the effect of single and repeated grapefruit juice ingestion relative to water on the oral pharmacokinetics of the nonmetabolized and P-glycoprotein-transported drug Talinolol in humans and to assess the potential impact of grapefruit juice ingestion on P-glycoprotein and intestinal uptake transporters. Methods The oral pharmacokinetics of 50 mg Talinolol was determined with water, with 1 glass of grapefruit juice (300 mL), and after 6 days of repeated grapefruit juice ingestion (900 mL/d) in 24 healthy white volunteers. MDR1 messenger ribonucleic acid and P-glycoprotein levels were measured in duodenal biopsy specimens obtained from 3 individuals before and after ingestion of grapefruit juice. Three commonly occurring polymorphisms in the MDR1 gene were also assessed. Results A single glass of grapefruit juice decreased the Talinolol area under the serum concentration-time curve (AUC), peak serum drug concentration (Cmax), and urinary excretion values to 56% (P < .001), 57% (P < .001), and 56% (P < .001), respectively, of those with water. Repeated ingestion of grapefruit juice had a similar effect (44% to 65% reduction; P < .01). Single or repeated juice ingestion did not affect renal clearance, elimination half-life, or time to reach Cmax (tmax). MDR1 messenger ribonucleic acid and P-glycoprotein levels in duodenal biopsy specimens were not affected by grapefruit juice. MDR1 genotypes (C1236T, G2677T/A, and C3435T) were not associated with altered Talinolol pharmacokinetics. Conclusion Because both single and repeated ingestion of grapefruit juice lowered rather than increased Talinolol AUC, our findings suggest that constituents in grapefruit juice preferentially inhibited an intestinal uptake process rather than P-glycoprotein. Moreover, grapefruit juice did not alter intestinal P-glycoprotein expression. Clinical Pharmacology & Therapeutics (2005) 77, 291–301; doi: 10.1016/j.clpt.2004.11.111
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P-glycoprotein inhibitor erythromycin increases oral bioavailability of Talinolol in humans.
International journal of clinical pharmacology and therapeutics, 2000Co-Authors: T. Gramatté, Reinhard Oertel, Krappweis J, Wilhelm KirchAbstract:Objective: Increased bioavailability of the P-glycoprotein (Pgp) substrates digoxin and cyclosporin due to erythromycin has been observed in vivo. The aim ofthe present study was to investigate the effect of orally administered erythromycin on the oral bioavailability of the β-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 (C max ) were significantly increased after administration of erythromycin compared to placebo, t max values were significantly reduced. The renal clearance (CL R ) of Talinolol was unchanged after co-administration of erythromycin and there was a small but statistically significant decrease in elimination half-life (t 1/2 ). 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.
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unexpected effect of verapamil on oral bioavailability of the β blocker Talinolol in humans
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Ute I. Schwarz, Reinhard Oertel, Thomas Gramatté, Annette Berndt, Jutta Krappweis, Oliver Von Richter, Wilhelm KirchAbstract:Purpose To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the β1-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 · h · mL−1 versus 945 ± 188 ng · h · 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. Clinical Pharmacology & Therapeutics (1999) 65, 283–290; doi:
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Unexpected effect of verapamil on oral bioavailability of the β‐blocker Talinolol in humans
Clinical pharmacology and therapeutics, 1999Co-Authors: Ute I. Schwarz, Reinhard Oertel, Thomas Gramatté, Annette Berndt, Jutta Krappweis, Oliver Von Richter, Wilhelm KirchAbstract:Purpose To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the β1-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 · h · mL−1 versus 945 ± 188 ng · h · 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. Clinical Pharmacology & Therapeutics (1999) 65, 283–290; doi:
Reinhard Oertel - One of the best experts on this subject based on the ideXlab platform.
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Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of Talinolol.
Clinical pharmacology and therapeutics, 2007Co-Authors: Ute I. Schwarz, Reinhard Oertel, Stephan Miehlke, Eberhard Kuhlisch, Richard B. Kim, H. Hanso, Hartmut Glaeser, Monika Hitzl, George K. Dresser, Wilhelm KirchAbstract:St John's wort (SJW) is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. Our study evaluated the effects of long-term SJW administration on oral and intravenous pharmacokinetics of the nonmetabolized in vivo probe of P-glycoprotein, Talinolol, in relation to intestinal P-glycoprotein expression. In a controlled, randomized study (N=9), the pharmacokinetics of oral (50 mg) and intravenous Talinolol (30 mg) was determined before and after 12 days SJW (900 mg daily, Jarsin 300®). Duodenal biopsies were taken and MDR1 genotypes assessed. SJW reduced the oral Talinolol bioavailability by 25% (P=0.049) compared with water control. A 93% increase in oral clearance (P=0.177) and a 31% reduction in area under the serum concentration time curve (AUC; P=0.030) were observed. Renal and nonrenal clearance (CLNR), elimination half-life, peak serum drug concentration (Cmax), and time to reach Cmax were not significantly altered. After intravenous Talinolol, SJW affected only CLNR (35% increase compared with water, P=0.006). SJW increased MDR1 messenger ribonucleic acid (mRNA) as well as P-glycoprotein levels in the duodenal mucosa. Subjects with the combined MDR1 genotype comprising 1236C>T, 2677G>T/A, and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and displayed an attenuated inductive response to SJW as assessed by Talinolol disposition. Long-term SJW decreased Talinolol AUC with a corresponding increase in intestinal MDR1 expression, suggesting that SJW has a major inductive effect on intestinal P-glycoprotein. Interestingly, the magnitude of induction appeared to be affected by MDR1 genotype. Clinical Pharmacology & Therapeutics (2007) 81, 669–678. doi:10.1038/sj.clpt.6100191; published online 28 March 2007
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Grapefruit juice ingestion significantly reduces Talinolol bioavailability.
Clinical pharmacology and therapeutics, 2005Co-Authors: Ute I. Schwarz, Reinhard Oertel, Diana Seemann, Stephan Miehlke, Eberhard Kuhlisch, Martin F. Fromm, Richard B. Kim, David G. Bailey, Wilhelm KirchAbstract:Objectives Our objectives were to evaluate the effect of single and repeated grapefruit juice ingestion relative to water on the oral pharmacokinetics of the nonmetabolized and P-glycoprotein-transported drug Talinolol in humans and to assess the potential impact of grapefruit juice ingestion on P-glycoprotein and intestinal uptake transporters. Methods The oral pharmacokinetics of 50 mg Talinolol was determined with water, with 1 glass of grapefruit juice (300 mL), and after 6 days of repeated grapefruit juice ingestion (900 mL/d) in 24 healthy white volunteers. MDR1 messenger ribonucleic acid and P-glycoprotein levels were measured in duodenal biopsy specimens obtained from 3 individuals before and after ingestion of grapefruit juice. Three commonly occurring polymorphisms in the MDR1 gene were also assessed. Results A single glass of grapefruit juice decreased the Talinolol area under the serum concentration-time curve (AUC), peak serum drug concentration (Cmax), and urinary excretion values to 56% (P < .001), 57% (P < .001), and 56% (P < .001), respectively, of those with water. Repeated ingestion of grapefruit juice had a similar effect (44% to 65% reduction; P < .01). Single or repeated juice ingestion did not affect renal clearance, elimination half-life, or time to reach Cmax (tmax). MDR1 messenger ribonucleic acid and P-glycoprotein levels in duodenal biopsy specimens were not affected by grapefruit juice. MDR1 genotypes (C1236T, G2677T/A, and C3435T) were not associated with altered Talinolol pharmacokinetics. Conclusion Because both single and repeated ingestion of grapefruit juice lowered rather than increased Talinolol AUC, our findings suggest that constituents in grapefruit juice preferentially inhibited an intestinal uptake process rather than P-glycoprotein. Moreover, grapefruit juice did not alter intestinal P-glycoprotein expression. Clinical Pharmacology & Therapeutics (2005) 77, 291–301; doi: 10.1016/j.clpt.2004.11.111
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Pharmacokinetics of oral Talinolol following a single dose and during steady state in patients with chronic renal failure and healthy volunteers.
International journal of clinical pharmacology and therapeutics, 2001Co-Authors: Krueger M, Reinhard Oertel, Achenbach H, Terhaag B, Haase H, Richter K, Rainer PreissAbstract:Objective: The objective of this study was to investigate the effect of renal impairment on the pharmacokinetics of the selective β 1 -receptor antagonist Talinolol. Methods: Pharmacokinetic data were obtained in 12 healthy volunteers, 12 patients with renal impairment and X patients with terminal renal insufficiency after the oral administration of 100 mg Talinolol and under steady state conditions (100 mg Talinolol daily). Concentrations of Talinolol in plasma, urine and dialysate during hemodialysis were measured with a validated HPLC-method. Results: Talinolol is absorbed quite rapidly from the gastrointestinal tract (t max 2.5 - 4 h). Steady state conditions were reached within 3-4 days depending on renal function. The calculated mean elimination half-life (t 1/2z ) in healthy volunteers (11 malc, 1 female) was about 12 h. After an oral dose of 100 mg, about 55% of the bioavailable Talinolol is eliminated unchanged in the urine. This fraction is reduced to 25% in patients with moderate to severe renal failure. A strong correlation was found between the renal elimination of Talinolol and creatinine clearance. In patients with renal failure, the delayed elimination leads to an increase in t 1/2z and to a decrease in the apparent total body clearance. Steady state trough levels (c mm ss ) in these patients are about 2.2-fold higher than in volunteers. The hemodialysability of Talinolol was low. Conclusion: The disposition of Talinolol shows a strong dependence on the renal function. On the basis of the kinetic data for Talinolol, dose reductions of 30 50% are recommended in subjects with moderate to severe renal impairment.
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induction of p glycoprotein by rifampin increases intestinal secretion of Talinolol in human beings a new type of drug drug interaction
Clinical Pharmacology & Therapeutics, 2000Co-Authors: Kristin Westphal, Reinhard Oertel, Anita Weinbrenner, Michael Zschiesche, G Franke, Manfred Knoke, Oliver Von Richter, Rolf Warzok, Peter Fritz, Thomas HachenbergAbstract:Background P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate Talinolol, a β1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings. Methods Pharmacokinetics of Talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1–messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years). Results During rifampin treatment, the areas under the curve of intravenous and oral Talinolol were significantly lower (21% and 35% P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous Talinolol (rs = 0.74; P < .001). Conclusions Rifampin induces P-glycoprotein–mediated excretion of Talinolol predominantly in the gut wall. Moreover, clearance of Talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism. (Clin Pharmacol Ther 2000;68:345-55.) Clinical Pharmacology & Therapeutics (2000) 68, 345–355; doi: 10.1067/mcp.2000.109797
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P-glycoprotein inhibitor erythromycin increases oral bioavailability of Talinolol in humans.
International journal of clinical pharmacology and therapeutics, 2000Co-Authors: T. Gramatté, Reinhard Oertel, Krappweis J, Wilhelm KirchAbstract:Objective: Increased bioavailability of the P-glycoprotein (Pgp) substrates digoxin and cyclosporin due to erythromycin has been observed in vivo. The aim ofthe present study was to investigate the effect of orally administered erythromycin on the oral bioavailability of the β-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 (C max ) were significantly increased after administration of erythromycin compared to placebo, t max values were significantly reduced. The renal clearance (CL R ) of Talinolol was unchanged after co-administration of erythromycin and there was a small but statistically significant decrease in elimination half-life (t 1/2 ). 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.
Peter Langguth - One of the best experts on this subject based on the ideXlab platform.
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Quantitative analysis of the effect of controlled-release formulation on nonlinear gastrointestinal absorption of P-glycoprotein substrate Talinolol using physiologically based pharmacokinetic absorption model
Journal of Drug Delivery Science and Technology, 2020Co-Authors: Satoru Suzuki, Peter Langguth, Yoshiyuki Shirasaka, Ren Okada, Akari Eguchi, Hisanao Kishimoto, Katsuhisa InoueAbstract:Abstract Oral absorption of Talinolol, a substrate of P-glycoprotein (P-gp), from a sustained-release (SR) formulation was reportedly decreased compared to that from an immediate-release (IR) formulation. The aim of this study was to predict and understand the effect of controlled-release formulation on the oral absorption of P-gp substrates by developing a physiologically based pharmacokinetic (PBPK) absorption model incorporating multiple kinetic parameters obtained from in vitro studies, using Talinolol as a model substrate. Simulation analysis using the developed PBPK absorption model indicated that the clinically observed marked decrease in the plasma concentration of Talinolol administered in an SR formulation occurs because the epithelial concentration of Talinolol in this case is lower than the Km value for P-gp. In other words, a decrease in the epithelial concentration of Talinolol due to SR dosage formulation may lead to greater impact of P-gp-mediated drug efflux, resulting in decreased intestinal drug absorption, whereas an increase in the epithelial concentration of Talinolol after administration in IR formulation may lead to saturation of P-gp. In conclusion, our strategy of simulation with a PBPK absorption model indicates that nonlinear saturable intestinal absorption characteristics can make SR formulations of P-gp substrates ineffective by decreasing the drug absorption.
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Species difference in the effect of grapefruit juice on intestinal absorption of Talinolol between human and rat. J Pharmacol Exp Ther 2010; 332
2016Co-Authors: Yoshiyuki Shirasaka, Hildegard Spahn-langguth, Peter Langguth, Erika Kuraoka, Takeo Nakanishi, Ikumi TamaiAbstract:Bioavailability of Talinolol, a 1-adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of Talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion-transporting polypeptide (Oatp)- and P-gp-mediated Talinolol absorption de-pends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated Talinolol transport was not inhibited by 2000 M naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a-mediated Talinolol transport with IC50 values of 343, 12.7, and 604 M, respec
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High-dose short-term administration of naringin did not alter Talinolol pharmacokinetics in humans.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2014Co-Authors: Mai Anh Nguyen, Ikumi Tamai, Petra Staubach, Peter LangguthAbstract:Abstract Naringin is considered the major causative ingredient of the inhibition of intestinal drug uptake by grapefruit juice. Moreover, it is contained in highly dosed nutraceuticals available on the market. A controlled, open, randomized, crossover study was performed in 10 healthy volunteers to investigate the effect of high-dose naringin on the bioavailability of Talinolol, a substrate of intestinal organic anion-transporting polypeptide (OATP)-mediated uptake. Following 6-day supplementation with 3 capsules of 350 mg naringin daily, 100 mg Talinolol were administered orally with 3 capsules of the same dietary supplement (1050 mg naringin) on the seventh day. This test treatment was compared to 100 mg Talinolol only (control). The results showed that short-term high-dose naringin supplementation did not significantly affect Talinolol pharmacokinetics. Geometric mean ratios of test versus control ranged between 0.90 and 0.98 for Talinolol cmax, AUC0−48h, AUC0−∞, t1/2 and Ae(0−48h). The high dose may provoke inhibition of the efflux transporter P-glycoprotein (P-gp) which counteracts the uptake inhibition. As disintegration and dissolution processes are required for the solid dosage form, dissolved naringin may arrive at the site of interaction after Talinolol is already absorbed. In conclusion, the effect of nutraceuticals on drug pharmacokinetics can deviate from that observed when administered as food component due to the different dose and dosage form.
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Quantitation of Talinolol in rat plasma by LC-MS-MS.
Journal of chromatographic science, 2010Co-Authors: Yoshiyuki Shirasaka, Peter Langguth, Ikumi TamaiAbstract:The aim of this study was to develop and validate an assay based on liquid chromatography-tandem mass spectrometry to quantitate Talinolol in rat plasma. After a simple protein precipitation step, separation was performed by reversed-phase liquid chromatography using gradient elution with acetonitrile-water-formic acid. Electrospray ionization in the positive ion mode with multiple reaction monitoring was used to analyze Talinolol employing propranolol as internal standard. The calibration curve for Talinolol was linear over the concentration range 1-250 ng/mL with a correlation coefficient > 0.995. The method was sensitive (limit of quantitation, 1 ng/mL) and had acceptable accuracy (85-115% of true values) and precision (intra- and inter-assay CV 78%. The method was successfully applied to the determination of the oral pharmacokinetics of Talinolol in rat.
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species difference in the effect of grapefruit juice on intestinal absorption of Talinolol between human and rat
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Yoshiyuki Shirasaka, Peter Langguth, Erika Kuraoka, Hildegard Spahnlangguth, Takeo Nakanishi, Ikumi TamaiAbstract:Bioavailability of Talinolol, a beta(1)-adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of Talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion-transporting polypeptide (Oatp)- and P-gp-mediated Talinolol absorption depends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated Talinolol transport was not inhibited by 2000 microM naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a-mediated Talinolol transport with IC(50) values of 343, 12.7, and 604 microM, respectively, in LLC-PK1 cell and Xenopus laevis oocyte systems. Because the naringin concentration in commercially prepared GFJ was found to be approximately 1200 microM, these results suggested that GFJ would reduce the intestinal absorption of Talinolol through inhibition of OATP1A2-mediated Talinolol uptake in humans, whereas an increase of Talinolol absorption is mainly through inhibition of Mdr1a-mediated efflux in rats. The rat intestinal permeability of Talinolol measured by the in situ closed loop method was indeed significantly increased in the presence of GFJ, whereas a significant decrease was observed with 6-fold diluted GFJ, in which the naringin concentration was approximately 200 microM. The present study indicated that the species difference in the effect of GFJ on intestinal absorption of Talinolol between humans and rats may be due to differences in the affinity of naringin for OATP/Oatp and MDR1/Mdr1 transporters between the two species.
Bernd Terhaag - One of the best experts on this subject based on the ideXlab platform.
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Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of Talinolol in healthy Chinese volunteers
European journal of clinical pharmacology, 2007Co-Authors: He Juan, Bernd Terhaag, Zang Cong, Zhang Bi-kui, Zhu Rong-hua, Wang Feng, Su Fen-li, Song Juan, Tang Jing, Peng Wen-xingAbstract:Objective To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker Talinolol.
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Determination of Talinolol in human plasma by high performance liquid chromatography-electrospray ionization mass spectrometry: application to pharmacokinetic study.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2007Co-Authors: Bernd Terhaag, Li-ying Yang, Bi-kui Zhang, Yun-gui Zhu, Juan Song, Jing Tang, Xiao-lei Liu, Wen-xing PengAbstract: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.
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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.
British journal of clinical pharmacology, 2006Co-Authors: Annika Bernsdorf, Bernd Terhaag, Thomas Giessmann, Christiane Modess, Danilo Wegner, Stefanie Igelbrink, Ute Hecker, Sierk Haenisch, Ingolf Cascorbi, Werner SiegmundAbstract:Aims To evaluate whether simvastatin influences (i) the intestinal expression of P-glycoprotein (P-gp) and MRP2, and (ii) the disposition of the β1-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 AUC0–∞ (r = 0.627, P = 0.039) and Cmax (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.
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Variability of Intestinal Expression of P-Glycoprotein in Healthy Volunteers as Described by Absorption of Talinolol from Four Bioequivalent Tablets
Journal of pharmaceutical sciences, 2003Co-Authors: Werner Siegmund, Bernd Terhaag, Michael Zschiesche, G Franke, Anna Hoffmann, Karen Ludwig, Georg Engel, Werner WeitschiesAbstract:ABSTRACT The β 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−∞ 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−∞ , 0.70–1.43 for C max ). The intra‐ and intersubject coefficients of variation for AUC 0−∞ 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−∞ 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.
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Stereoselective disposition of Talinolol in man
Journal of pharmaceutical sciences, 2002Co-Authors: Michael Zschiesche, Bernd Terhaag, Thomas Gramatté, G Franke, Heyo K. Kroemer, Girum Lakew Lemma, Klaus‐jürgen Klebingat, Anna Hoffmann, Werner SiegmundAbstract:Abstract The disposition of the β‐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 Cl int values of S(−) were higher than of R(+) Talinolol; 0.1 μM 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.
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Stereoselective disposition of Talinolol in man
Journal of pharmaceutical sciences, 2002Co-Authors: Michael Zschiesche, Bernd Terhaag, Thomas Gramatté, G Franke, Heyo K. Kroemer, Girum Lakew Lemma, Klaus‐jürgen Klebingat, Anna Hoffmann, Werner SiegmundAbstract:Abstract The disposition of the β‐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 Cl int values of S(−) were higher than of R(+) Talinolol; 0.1 μM 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.
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Intestinal secretion of intravenous Talinolol is inhibited by luminal R-verapamil.
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Thomas Gramatté, Reinhard OertelAbstract:Objective To examine the secretion of the β1-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 μmol/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 μg/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 μg/30 cm · 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. Clinical Pharmacology & Therapeutics (1999) 66, 239–245; doi:
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unexpected effect of verapamil on oral bioavailability of the β blocker Talinolol in humans
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Ute I. Schwarz, Reinhard Oertel, Thomas Gramatté, Annette Berndt, Jutta Krappweis, Oliver Von Richter, Wilhelm KirchAbstract:Purpose To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the β1-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 · h · mL−1 versus 945 ± 188 ng · h · 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. Clinical Pharmacology & Therapeutics (1999) 65, 283–290; doi:
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Unexpected effect of verapamil on oral bioavailability of the β‐blocker Talinolol in humans
Clinical pharmacology and therapeutics, 1999Co-Authors: Ute I. Schwarz, Reinhard Oertel, Thomas Gramatté, Annette Berndt, Jutta Krappweis, Oliver Von Richter, Wilhelm KirchAbstract:Purpose To quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P-glycoprotein on oral pharmacokinetics of the β1-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 · h · mL−1 versus 945 ± 188 ng · h · 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. Clinical Pharmacology & Therapeutics (1999) 65, 283–290; doi:
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Direct demonstration of small intestinal secretion and site‐dependent absorption of the β‐blocker Talinolol in humans
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Thomas Gramatté, Reinhard Oertel, Bernd Terhaag, Wilhelm KirchAbstract:Objective To examine the relevance of site-dependent small intestinal absorption for incomplete intestinal absorption of the poorly metabolized β1-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 95 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 μg/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. Clinical Pharmacology & Therapeutics (1996) 59, 541–549; doi: