Michael Zschiesche

Induction of P‐glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction

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.

Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P‐glycoprotein

Recent data indicated that disposition of oral digoxin is modulated by intestinal P‐glycoprotein. The cardioselective β‐blocker talinolol has been described to be secreted by way of P‐glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug‐drug interaction based on a competition for intestinal P‐glycoprotein.

Carbamazepine regulates intestinal P‐glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans

The antiepileptic drug carbamazepine is known to be an inducer of cytochrome P450 (CYP) 3A4 after binding to the nuclear pregnane X receptor. To evaluate whether it also regulates the multidrug transporter proteins P‐glycoprotein (P‐gp) and multidrug resistance protein MRP2 in humans, duodenal expression of multidrug resistance gene MDR1 messenger ribonucleic acid (mRNA) and MRP2 mRNA, content of P‐gp and MRP2, and disposition of the nonmetabolized P‐gp substrate talinolol after intravenous (30 mg) and long‐term oral administration (100 mg for 19 days) were assessed in 7 healthy subjects (age, 23–35 years; body weight, 64–93 kg) before and after comedication of carbamazepine (600 mg for 14–18 days).

CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects

Clinical trials have indicated that the combined β‐ and α‐adrenergic receptor blocker carvedilol improves the survival rate in patients with advanced chronic heart failure. The objective of our study was the identification and quantification of factors that modulate steady‐state serum concentrations of carvedilol and its enantiomers and that may influence therapeutic efficacy and safety.

The talinolol double-peak phenomenon is likely caused by presystemic processing after uptake from gut lumen.

Purpose.Evaluation of the double-peak phenomenon during absorption of the β1-selective blocker talinolol relative to paracetamol, which is well absorbed from all parts of the gut, and relative to vitamin A, which is absorbed via the lymphatic pathway.Methods.Talinolol was given with paracetamol and retinyl palmitate in fast-disintegrating, enteric-coated, and rectal soft capsules to 8 fasting male healthy subjects (21–29 years, 68–86 kg). To evaluate whether the talinolol double-peak is associated with processes of food absorption, a breakfast was served 1 h after administration of a fast disintegrating capsule.Results.Bioavailability of talinolol in enteric-coated and rectal capsules was significantly reduced by about 50% and 80%, respectively, despite unchanged bioavailability of paracetamol. Double-peaks appeared after 2–3 h and 4–6 h with talinolol given as fast-liberating capsules. Food increased the maximum concentrations significantly (223 ± 76 μg/ml vs. 315 ± 122 μg/ml, p ‹ 0.05) and shifted the second peak of talinolol to shorter tmax values (3.8 ± 1.2 h vs. 2.1 ± 0.6 h, p ‹ 0.05), which was associated with faster absorption of retinyl palmitate. Pharmacokinetic model fits showed that about half of the oral talinolol dose given with and without meal is drained from the intestine via a presystemic storage compartment.Conclusions.The double-peak phenomenon of talinolol is likely caused by a presystemic storage compartment, which represents the complex interplay of heterogeneous uptake and kick-back transport processes along the intestinal-hepatic absorption pathway.

Effect of levothyroxine administration on intestinal P‐glycoprotein expression: Consequences for drug disposition*

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.

Kinetics of propiverine as assessed by radioreceptor assay in poor and extensive metabolizers of debrisoquine

SummaryA pharmacokinetic study with 30 mg propiverine p.o. was performed in healthy volunteers (10 males, 6 females, age 36–56 years, body weight 55–100 kg, body height 162–184 cm, Broca index 0.96–1.19). 8 of them were poor and 8 extensive metabolizers of the debrisoquine type hydroxylation polymorphism. The total anticholinergic activity of the parent compound and active metabolites was measured with a radioreceptor assay calibrated with the metabolite M2. The affinity of this metabolite to the muscarinic receptors was similar to that of atropine. The urinary excretion of 3 major metabolites was determined with TLC and densitometry. Arterial blood pressure, heart rate, diameter of pupils, accommodation and parotic salivary flow were also measured.The concentrations of anticholinergic equivalents of propiverine were below 1 ng/ml of M2. 1.4–6.0% of the dose were excreted as N-oxidized metabolites into the urine. The poor and extensive metabolizers of debrisoquine did not differ significantly with regard to the concentration time behaviour of the active drug components, pattern of major metabolites, adverse drug reactions or any pharmacodynamic parameters measured.

Pharmacokinetic Interactions Between Isoniazid and Theophylline in Rats

Abstract— Pharmacokinetic interactions between isoniazid and theophylline were studied in male Wistar rats, 206±17 g. Concomitant oral administration of 2 × 5 mg kg−1 isoniazid accelerated slightly the disposition of theophylline (10 mg kg−1, i.v.) whereas 2 × 25 mg kg−1 isoniazid slowed it marginally. The differences in distribution volume, systemic clearance and area under the concentration‐time curve (AUC) between the high and the low dose, however, were statistically significant. One week pretreatment with 10 mg kg−1 isoniazid tended towards inhibition (significant decrease of systemic clearance, increase of AUC) and 50 mg kg−1 to acceleration (decrease of half‐life, mean residence time and AUC, increase of systemic clearance) of theophylline disposition. After oral pretreatment with 20 mg kg−1 theophylline, neither the kinetics of free isoniazid (50 mg kg−1, i.v.) and the amount acetylated nor the acetylation indices differed from the controls. There was no evidence that concomitant or subacute administration of different doses of isoniazid affects major metabolic pathways of theophylline or that prolonged theophylline treatment interacts with the N‐acetylation capacity.

Relative bioavailability and pharmacodynamic effects of methantheline compared with atropine in healthy subjects

ObjectivesMethantheline is a strong muscarinic receptor blocking drug used in the treatment of overactive bladder syndrome, hypersalivation and hyperhidrosis. To provide basic information on the pharmacokinetics, magnitude of pharmacodynamic (PD) effects and their correlations with plasma concentrations, we performed a clinical study in 12 healthy subjects receiving methantheline as immediate-release coated tablets (IR) or in watery solution (SOL) in comparison with atropine and placebo tablets.MethodsThe pharmacokinetics and influence of methantheline, atropine and placebo on salivation and accommodation and pupil function (pupillometry: diameter, response to light flash) were studied in a randomized, controlled study after the administration of 100xa0mg methantheline bromide as IR and in SOL (phase 1) and 1.0xa0mg atropine sulphate and placebo (phase 2).ResultsMethantheline reached maximum plasma concentrations of approximately 25xa0ng/ml after 2.5–3xa0h and was eliminated at an apparent half-life of approximately 2xa0h. There was no pharmacokinetic (PK) bioequivalence of methantheline IR and SOL. The ratio IR/SOL (90xa0% confidence interval) were 0.892 (0.532–1.493) for AUC0-∞ and 0.905 (0.516–1.584) for maximum plasma concentration. The PD effects of both forms were nearly equivalent with a IR/SOL ratio of 1.015 (0.815–1.262) for salivation, which is the most susceptible characteristic. Methantheline reduced salivation at a potency (methantheline concentration at half maximum effects, EC50) of 5.5xa0ng/ml in accordance with it plasma concentration. The antimuscarinic effects observed after methantheline administration were stronger and persisted longer than those following the administration of atropine.ConclusionsMethantheline is slowly absorbed but rapidly eliminated in humans, and it exerts a strong effect on salivation which is closely associated with its plasma concentrations following a standard sigmoid PD model. Immediate-release tablets and a watery solution of methantheline are equivalent in terms of major PD effects (salivation, pupil function, heart rate) despite its high PK variability.

Rifampin impairs steady‐state bioavailability of talinolol: Potential role of P‐gp

Clinical Pharmacology & Therapeutics (1999) 65, 180–180; doi: