The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism.

The calcium channel blocker nifedipine is metabolized by cytochrome P450 3A4, which is present in liver and mucosa of the small bowel. Cytochrome P450 3A4 is inducible by the tuberculostatic rifampin in liver and the small bowel. The contribution of gut wall metabolism to total clearance of nifedipine before and during induction has not been determined in detail.

Effect of chlormethiazole on hepatic monooxygenases activity in vivo.

Chlormethiazole is a strong inhibitor of cytochrome P-450-dependent monooxygenases in isolated human liver microsomes. To assess its effect in vivo, we measured the pharmacokinetic parameters of antipyrine (1.2 g orally) and tolbutamide (0.

Divergent effects of different enzyme-inducing agents on endogenous and exogenous testosterone.

The effects of three different enzyme-inducing drugs (antipyrine 1200 mg, phenobarbital 100 mg, rifampicin 600 mg per day for 7 days) on plasma and urinary testosterone concentrations, plasma gonadotropin levels, antipyrine kinetics, and urinary 6 beta-hydroxycortisol excretion were studied in 18 healthy volunteers. Changes in plasma and urinary testosterone concentrations following exogenous testosterone undecanoate (TU) were also investigated. Although both antipyrine and rifampicin increased antipyrine clearance by about 60%, they produced contrary effects on testosterone: antipyrine lowered the total morning plasma testosterone and plasma testosterone AUC following TU, while rifampicin led to increases of about 20% and 78%, respectively.

Ranitidine treatment and cortisol metabolism in man.

Experimental evidence suggested that H2-receptor antagonists may inhibit not only hepatic but also adrenal cytochrome P-450 dependent monooxygenases. Therefore, the effects of ranitidine (150 mg b.i.

Pharmacokinetics of encainide in patients with cirrhosis.

The pharmacokinetics of encainide were investigated in 10 patients with cirrhosis and 10 matched controls following single intravenous (IV, 25 mg), single oral (so, 25 mg), and multiple oral (mo, 25 mg thrice daily over 5 days) dosing. The hepatic oxidative drug-metabolizing enzyme capacity and its inducibility were assessed by antipyrine elimination and 6-beta-hydroxycortisol excretion. Eight controls and nine patients were of the extensive metabolizer phenotype (EM), as assessed by the sparteine metabolic ratio.

Effect of antipyrine and phenobarbital on renal gamma-glutamyltransferase excretion in human urine.

Serum gamma-glutamyltransferase is used as a marker of hepatic enzyme induction. The kidney contains high activities of gamma-glutamyltransferase in the brush border membrane of the proximal tubule, from which it is released into urine. This study investigated the effect of phenobarbital and antipyrine, two inducers of hepatic monoxygenases and gamma-glutamyltransferase, on the urinary excretion of renal gamma-glutamyltransferase.

Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam.

The pharmacokinetics of nitrazepam and temazepam were investigated in 16 healthy volunteers before and after seven days of the administration of rifampin 600 mg/d and/or probenecid 500 mg/d. In order to determine the endoplasmatic reticulum enzyme function, 6-beta-hydroxycortisol excretion and antipyrine pharmacokinetic parameters were evaluated. After the administration of rifampin, the total body clearance of antipyrine and nitrazepam increased by 87% and 83%, respectively.

Effect of oral contraceptive steroids on the pharmacokinetics of phenprocoumon.

1. The effect of chronic administration of oral contraceptive steroids (OCS) on the pharmacokinetics of the oral anticoagulant phenprocoumon was investigated in seven healthy females. 2.

Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease.

Induction of hepatic monooxygenases reflected by 7-ethoxycoumarin O-deethylase has been proposed to be associated with the initiation of liver damage. This study investigated a possible correlation between 7-ethoxycoumarin O-deethylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase and benzypyrene hydroxylase activity in liver biopsy specimens of 31 patients with liver disease and antipyrine elimination, an in vivo parameter of hepatic monooxygenase activity. No correlation was found between the enzyme activities and antipyrine clearance or half-life.

The effects of frusemide and probenecid on the pharmacokinetics of phenprocoumon.

We have studied the pharmacokinetics of phenprocoumon with and without co-administration of frusemide and probenecid in two groups of 17 healthy volunteers. Frusemide 40 mg b.i.

Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function.

Three different studies were conducted to assess the pharmacokinetics of moclobemide in subjects with conditions complicating dose determination. The first examined the absorption and disposition of moclobemide in an elderly population and compared these with results obtained in a group of normal young subjects. No significant differences were found between the groups in the intravenous (i.

Pharmacokinetics after a single oral dose of bopindolol in patients with cirrhosis.

The plasma concentration-time curve of the hydrolysis product of bopindolol has been investigated in 14 patients with cirrhosis and in 15 healthy volunteers given a single oral dose of 2 mg bopindolol. Cirrhosis was confirmed by history and clinical examination or liver biopsy. The time to maximum concentration, maximum concentration and AUC of hydrolyzed bopindolol were similar in the patients and controls.

[Probenecid affects liver metabolism].

The effect of probenecid on the pharmacokinetics of phenprocoumon (PPC) given as a single oral or intravenous dose, on the vitamin-K-dependent protein-C-antigen, and on the pharmacokinetics of antipyrine and 6 beta-hydroxycortisol was determined in 14 healthy volunteers. Probenecid caused a 75% decrease in urinary excretion of PPC and PPC-glucuronide and shortened the plasma half-life of PPC significantly (by about 35%). The results after oral and intravenous administration of PPC did not differ significantly.

Cimetidine and the immuno-response in healthy volunteers.

We compared the immunologic measurements from treatment of 12 healthy volunteers (six male, six female) with 800 and 1,600 mg cimetidine. In the first trial 800 mg cimetidine was administered daily to the volunteers over a period of 7 d; after an interruption of 2 months, 1,600 mg of cimetidine was applied daily for 21 d. The most striking result of our study was an increased mitogen-induced lymphocyte proliferation.

The immunomodulatory potency of cimetidine in healthy volunteers.

The effect of cimetidine, a histamine H2 receptor antagonist, was investigated in 12 healthy volunteers over a period of six weeks. Cimetidine was administered orally in a daily doses of 1,600 mg during the first three weeks of evaluation. Significant alterations in values of immunoglobulins (IgG, IgA), complement (C3), B-lymphocytes and T-helper cell counts were found after cimetidine intake.

Effect of aminophylline on cisplatin nephrotoxicity in the rat.

1. The effect of the methylxanthine aminophylline on cisplatin (5 mg kg-1 i.v.

Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements.

In a randomized placebo-controlled study 12 healthy volunteers were treated for 1 wk each with 10 mg of nifedipine four times daily plus placebo or the same dose of nifedipine concurrently with 40 mg of famotidine once a day. Famotidine did not significantly alter pharmacokinetic parameters of nifedipine. Determination of systolic time intervals showed that the preejection period and the ratio of the preejection period and the left ventricular ejection time were significantly reduced by administration of nifedipine plus placebo.

Effects of felodipine on plasma digoxin levels and haemodynamics in patients with heart failure.

The interaction between felodipine and digoxin was studied after a single oral dose and at steady state in 14 patients with congestive heart failure. Felodipine (10 mg) was randomly given as an extended release (FER) tablet in a double-blind, placebo-controlled, cross-over fashion. In addition, felodipine (10 mg) was given openly as a plain tablet, following the double-blind period.

[Mechano- and impedance cardiography parameters in patients with heart failure in administration of a calcium antagonist. The significance of the Heather index].

By means of impedance- and mechanocardiography the effect of the calcium-channel blocker nisoldipine on the circadian course of hemodynamic parameters was measured in a placebo-controlled randomized double-blind study in 18 patients with heart failure (NYHA II). A significant effect of nisoldipine on left ventricular function was observed after 2 h but not any more 6 h following the administration of the drug. This effect was expressed by a reduction of the pre-ejection period (PEPc) and PEP/LVET in the systolic time intervals (STI) and a rise in stroke volume (delta V) and cardiac output (CO), as well as an increase of the Heather-index in impedance cardiography (ICG).

Immunomodulation of cimetidine in healthy volunteers.

The effect of cimetidine, a histamine H2-receptor antagonist, on the immune system in man was investigated in 11 healthy volunteers. Cimetidine was administered orally in daily doses of 800 mg for a period of 7 days. At the end of the administration period the number of peripheral CD8+ (cytotoxic/suppressor) cells had diminished significantly (P less than 0.

Urinary excretion of 6 beta-hydroxycortisol and the time course measurement of enzyme induction in man.

The effect of enzyme induction by antipyrine, phenobarbitone and rifampicin on the time-course of urinary 6 beta-hydroxycortisol (6 beta-OHC) excretion was investigated in healthy volunteers. The drugs were given chronically for either seven or 14 days. Significant increases in 6 beta-OHC excretion were observed after 4 days administration of antipyrine (1.

Cisapride-cimetidine interaction: enhanced cisapride bioavailability and accelerated cimetidine absorption.

The pharmacokinetic interaction between the gastrointestinal motility-stimulating substance cisapride and the H2-antagonist cimetidine was examined in 8 healthy volunteers (25 +/- 2 years of age). Steady-state kinetics of both substances were investigated after separate 1-week treatments of oral cisapride, 10 mg t.i.

Kinetics of oral and intravenous mexiletine: lack of effect of cimetidine and ranitidine.

The pharmacokinetics of mexiletine, a Class I antiarrhythmic drug, was investigated in 6 healthy volunteers after single oral doses and 15 min intravenous infusions of 3 mg/kg. Cimetidine and ranitidine are commonly used H2-receptor antagonists, which interact adversely with many drugs, e.g.

Digitoxin in patients with hepatorenal insufficiency after repeated oral administration.

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy.