Gerd Franke

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.

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.

Disposition kinetics of metronidazole in children

SummaryThe pharmacokinetics of metronidazole was studied in 20 paediatric patients aged 6 weeks and 4 to 14 years, who had trichomonal vaginitis or an anaerobic bacterial infection. The dosage of metronidazole was about 10 or 20 mg/kg b.i.d. orally. The serum concentrations found in children and the corresponding calculated kinetic parameters were similar to those in adults after intake of an equal, weight-related dose. Metronidazole shows rapid diffusion into the saliva with a concentration ratio of about 1.0. This can provide the basis for an efficient non-invasive method of drug monitoring.

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.

Drug oxidation and N-acetylation in rats pretreated with subtoxic doses of streptolysin O

SLO in sublytic doses (100 HU/kg body wt) depressed the hepatic microsomal cytochrome P450 and aminopyrine-N-demethylase but increased significantly the cytosolic N-acetyltransferase after acute and subacute (5 days) pretreatment of male Wistar rats. Aniline hydroxylase was reduced after acute and unchanged after subacute pretreatment. The effects of SLO on the oxidative enzymes and drug N-acetylation might have been caused by the membranal and immunological properties of the toxin.

Effects of streptolysin O, picibanil (OK 432) and interferon α2A on cytochrome P-450-dependent monooxygenases and arylamine N-acetyltransferase in rat liver

Streptolysin O, a thiol-activated exotoxin from group A beta-haemolytic streptococci, caused a dose-dependent depression of aniline hydroxylase, aminopyrine N-demethylase and ethylmorphine N-demethylase activities when added into the hepatic microsomal mixtures from male rats at concentrations 0.02-0.4 HU/mL in vitro. The activities of 7-ethoxycoumarin O-deethylase, 7-ethylresorufin O-deethylase and 7-pentylresorufin O-depentylase were not altered with the used concentrations of the toxin. Specific antibody against haemolytic action of streptolysin O added to incubation mixtures in vitro was not able to protect streptolysin-sensitive monooxygenases from the inhibition. The addition of streptolysin O (0.01-0.8 HU/mL) into the cytosol-containing medium did not significantly influence the activity of procainamide N-acetyltransferase. Immunomodulators picibanil (OK 432) and human recombinant interferon alpha 2A which are known to suppress oxidative metabolism in vivo in humans and animals, were without effect either on the cytochrome P-450-dependent monooxygenases or on the N-acetyltransferase activity when administered in vitro at the doses real in their clinical application (0.001-0.1 KE/mL of picibanil and 10-500 U/mL of alpha-interferon).

Clinical use of reversal of mydriasis by dapiprazole

SummaryBackground: Dapiprazole hydrochloride is an alpha-1-adrenergic inhibitor that anticipates the mydriatic effect of phenylephrine in dilator muscle receptors in a competitive way. The aim of this study was to determine for which indications for mydriasis pupil dilation by phenylephrine alone is sufficient and if the reversal by dapiprazole is convenient and the practical. Material and method: In 286 eyes of 147 outpatients, the pupil was dilated for fluorescein angiography – FLA (100 eyes of 50 patients), examination of the fundus – Fd (99 eyes of 52 patients), central argon laser coagulation – cALC (64 eyes of 32 patients), peripheral argon laser coagulation – pALC (16 eyes of 9 patients) and Nd:YAG capsulotomy (7 eyes of 4 patients) with phenylephrine 10 % eye drops, followed by reversal by dapiprazole 0.5 %. The width and mobility of the pupil were tested at intervals of 10 min. When mydriasis by phenylephrine was insufficient, tropicamide was applied additionally. Results: In 98 % of FLA with scanning laser ophthalmoscope, 75 % of cALC, 76 % of Fd, 62 % FLA with fundus camera and 38 % of pALC, mydriasis could be reached that was sufficient for the indication. Diabetics showed significantly more sluggish pupil mobility (t1/2: P < 0.05 mydriasis, P < 0.005 reversal). The mean duration after using dapiprazole until reaching the starting value ( ± 1 mm) of the pupil was 44.3 ± 26.3 min. In 86 % of the examined eyes, the pupil reached its starting value within 1 h. The subjective degree of satisfaction with the application of dapiprazole was “satisfied” to “very satisfied” (5.4 ± 1.4 points on a scale from 1 to 7 points). Discussion and conclusion: In fundus examination, fluorescein angiography by a laser scanner, diagnostic retinal examination and central laser coagulation, the combination phenylephrine/dapiprazole was most suitable. In our opinion, the combination is less suitable for peripheral argon laser coagulation and fluorescein angiography using a fundus camera.ZusammenfassungHintergrund: Dapiprazolhydrochlorid ist ein alpha-1-adrenerger Blocker, der die mydriatische Wirkung von Phenylephrin an den Rezeptoren der glatten Muskulatur des M. dilatator pupillae direkt kompetitiv antagonisiert. Ziel der vorliegenden Studie war festzustellen, bei welchen Indikationen zur Mydriasis eine Pupillenerweiterung alleine mit Phenylephrin ausreichend und damit die Antagonisierung mittels Dapiprazol in der praktischen Anwendung sinnvoll ist. Patienten und Methode: In einer prospektiven Studie wurden 286 Augen von 147 ambulanten Patienten zunächst nur mit Phenylephrin 10 % AT weitgetropft für Fluoreszenzangiographien – FLA (100 Augen von 50 Patienten), Fundusuntersuchungen – Fd (99 Augen von 52 Patienten), zentrale Argonlaserkoagulationen – zALK (64 Augen von 32 Patienten), periphere Argonlaserkoagulationen – pALK (16 Augen von 9 Patienten) und Nd:YAG-Laser Kapsulotomien (7 Augen von 4 Patienten). Es wurde beurteilt, ob die Mydriasis für die geplante Untersuchung bzw. Behandlung ausreichend war. Bei unzureichender Mydriasis wurde zusätzlich ein Parasympathikolytikum getropft. Anschließend erfolgte eine Antagonisierung mit Dapiprazol 0,5 % AT. Ergebnisse: Eine für die Indikation ausreichende Mydriasis wurde erreicht in 98 % bei FLA mittels Laserscanner, 75 % bei zALK, 76 % bei Fd, 62 % bei FLA mittels Funduskamera und 38 % bei pALK. Die mittlere Zeitdauer nach Dapiprazolanwendung bis zum Erreichen des Ausgangspupillenwertes ( ± 1 mm) betrug 44,3 ± 26,3 min. 86 % aller Patienten erreichten spätestens 1 h nach Dapiprazolanwendung wieder die Ausgangspupillenweite. Der subjektive Zufriedenheitsgrad der Patienten lag bei „zufrieden“ mit Tendenz zu „sehr zufrieden“ (5,4 ± 1,4) auf einer Punkteskala von 1 bis 7. Diskussion: Die besten Anwendungseignungen der Kombination: Phenylephrin/Dapiprazol waren Fluoreszenzangiographien mittels Laserscanner, Fundusuntersuchungen sowie zentrale Argonlaserkoagulationen. Bei peripheren Argonlaserkoagulationen und bei Fluoreszenzangiographien mit einer Funduskamera war wesentlich häufiger die zusätzliche Applikation von Tropicamid erforderlich.

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

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