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. We therefore investigated the nifedipine-rifampin interaction, with special emphasis on the contribution of gut wall metabolism to total metabolism of nifedipine before and during administration of rifampin. Pharmacokinetics of nifedipine were studied in six healthy volunteers on separate days by administration of 20 micrograms/kg body weight nifedipine iv and 20 mg nifedipine orally before and after 7 days of rifampin treatment (600 mg/day). Enzyme induction did not significantly alter pharmacokinetics of nifedipine after iv administration. In contrast, oral clearance of nifedipine increased from 1.5 +/- 0.2 liters/min to 20.9 +/- 8.3 liters/min (p < 0.01) and bioavailability decreased from 41.2 +/- 5.4% to 5.3 +/- 2.7% (p < 0.001). Although hepatic extraction of nifedipine was not significantly altered during induction (47.4 +/- 6.6% versus 67.4 +/- 20.2%; ns), the calculated extraction of nifedipine in gut wall mucosa increased from 21.8 +/- 13.3% to 75.8 +/- 28.2% (p < 0.05). We conclude that there is a relevant interaction between nifedipine and rifampin. The reduction of nifedipine bioavailability during enzyme induction is most likely due to rifampin-induced gut wall metabolism.

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 (0.5 g i.v.) before and after administration of chlormethiazole 314 mg b.d. for 2 days to 8 healthy volunteers. The elimination of neither substance was affected, indicating that chlormethiazole did not inhibit in vivo the cytochrome P-450 isozymes responsible for the elimination of antipyrine and tolbutamide.

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.d. over 14 days) on cortisol metabolism and antipyrine clearance have been investigated in nine healthy volunteers. Urinary excretion of 6 beta-hydroxycortisol (6 beta-OHC) and 17-hydroxycorticosteroids (17-OHCS) remained unaffected by ranitidine pretreatment, as did the calculated 6 beta-OHC/17-OHCS ratio. Only marginal effects were observed on antipyrine kinetics and metabolite formation. We conclude that neither adrenal production of corticosteroids nor their hepatic metabolism is affected by ranitidine administration.

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. By contrast, phenobarbital did not significantly alter the endogenous and exogenous plasma testosterone concentrations, but it increased the urinary excretion of testosterone by more than 60%. The other two enzyme inducers did not alter this parameter. Gonadotropin levels remained unchanged. The results indicate that different enzyme-inducing agents exert divergent effects on endogenous and exogenous testosterone concentrations and suggest that the effect of enzyme induction on endogenous testosterone depends on the type of microsomal enzyme-inducing drug used rather than on the extent of the induction achieved.

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. Statistics was performed in EM only. The antipyrine half-life was significantly longer and clearance was significantly lower in patients with cirrhosis. Following IV administration, no significant differences in encainide half-life clearance, volume of distribution, or the area under the plasma concentration time curve (AUC) were observed between patients and controls. Following so and mo, there was a fourfold reduction in the oral clearance in cirrhotics. Thus, encainide bioavailability was increased in cirrhosis. Whereas the AUC of encainide was significantly higher in patients, no differences were observed in its active metabolites, O-desmethyl-encainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Plasma concentrations of encainide and its metabolites after 3 and 5 days of mo suggested steady-state conditions after 3 days of oral dosing. No change in antipyrine elimination and 6-beta-hydroxycortisol excretion following mo occurred. There was no relationship between parameters of encainide and antipyrine elimination. In conclusion, even though the elimination of encainide was reduced in patients with cirrhosis, plasma levels of the pharmacologically active metabolites, ODE and MODE, were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

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. Three groups (n = 6) of healthy male volunteers received 100 mg phenobarbital for 7 and 14 days and 1200 mg antipyrine for 7 days, respectively. Antipyrine and phenobarbital increased antipyrine elimination, serum gamma-glutamyltransferase, and the urinary excretion of renal gamma-glutamyltransferase, whereas urinary beta-N-acetylglucosaminidase, beta-glucuronidase, and total protein and glucose excretion were unchanged. No correlation was found between serum and urinary gamma-glutamyltransferase or both enzymes and antipyrine elimination. Increases in antipyrine elimination were positively correlated to increases in serum, but not urinary gamma-glutamyltransferase. The findings suggest that antipyrine and phenobarbital increase urinary gamma-glutamyltransferase excretion. However, the increase in urinary gamma-glutamyltransferase does not reflect the magnitude of hepatic enzyme induction.

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. After the combined treatment with rifampin and probenecid, the elimination of the two drugs was also increased, even though to a lesser extent (33%, 31%). After the administration of probenecid only, the total clearances of antipyrine and nitrazepam were decreased by 22% and 25%, respectively. The urinary clearance of the antipyrine metabolites also decreased. In norantipyrine and 4-OH-antipyrine, this was due to a significant reduction of glucuronide fraction (211 +/- 32 to 159 +/- 26 mg, and 259 +/- 39 to 191 +/- 25 mg). The sulphate fraction of norantipyrine increased by 18% and that of 4-OH-antipyrine by 21%. Apart from a reduced excretion of the glucuronide fraction, the pharmacokinetics of temazepam were neither altered significantly by probenecid nor by rifampin. According to the outcome of this investigation, probenecid seems to bring about not merely an inhibition of phase II but also an inhibition of phase I metabolization.

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. Plasma concentrations of phenprocoumon and the urinary recovery of unchanged as well as conjugated drug were measured following a single oral dose of 0.22 mg kg-1. A group of seven non-smoking, drug-free women matched for age and body weight served as controls. 3. Administration of OCS was associated with a significant increase in the clearance of phenprocoumon from 1.6 +/- 0.7 to 2.0 +/- 0.7 ml min-1 kg-1 (P less than 0.05). The urinary recovery of phenprocoumon glucuronide was significantly higher in OCS users (21.0 +/- 16 vs 14.0 +/- 10 (% of dose); P less than 0.05). No difference in plasma protein binding of phenprocoumon was observed, being 99.2 +/- 0.07 in both groups. 4. The accelerated glucuronidation of phenprocoumon in OCS users suggests the need for careful monitoring of the anticoagulatory response in these subjects, especially when the OCS are withdrawn.

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. When microsomal enzyme activities were compared with the formation rate of 4-hydroxyantipyrine, 3-methylhydroxyantipyrine, and norantipyrine, a correlation was found only between benzo[alpha]pyrene hydroxylase and 3-methylhydroxyantipyrine (r = 0.89; p less than 0.0005). There was also a correlation between 7-ethoxycoumarin O-deethylase and reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase (0.56; p less than 0.05). Our data suggest that antipyrine elimination is not related to 7-ethoxycoumarin O-deethylase activity in liver disease. However, the formation rate of antipyrine metabolites, rather than antipyrine half-life and clearance, may correlate with the activity of certain microsomal enzymes.

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.v.) parameters of disposition, and no differences with regard to disposition of the metabolite, Ro 12-8095. In addition, the minimum steady-state concentrations of moclobemide and the main plasma metabolite did not differ between the elderly and younger patients. In the second study, clearance tests in patients with cirrhosis of the liver confirmed that hepatic function is drastically reduced in this group of patients; it is therefore possible that moclobemide absorption and distribution might be influenced. In only 3 of the 12 patients investigated, slowly declining plasma concentrations after administration pointed to a severely limited elimination capacity for moclobemide. In the remaining 9 subjects, average values of several parameters changed significantly (t 1/2 beta, MRT and C1), whereas Vss and renal clearance were not significantly altered. In patients with kidney dysfunction, there were no differences in kinetics between patients undergoing hemodialysis and those who were not. Compared with normal healthy volunteers, no differences were found for renal patients, with the exception of the mean absorption time, which was significantly prolonged. From these studies it can be concluded that, pharmacokinetically, neither age nor renal impairment require adjusting the dosage of moclobemide. Patients with liver cirrhosis, however, need to have the usual dose reduced to one half or one third, or else the dosage intervals can be increased to prevent cumulation.

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.d. for 7 days did not interact with phenprocoumon to a significant extent. Probenecid 500 mg q.i.d. for 7 days significantly accelerated the overall elimination of phenprocoumon, as indicated by a decrease in AUC from 295 to 157 micrograms.h.ml-1, and a reduction in the fraction of the dose excreted by the kidneys. The data are consistent with inhibition of the glucuronidation of phenprocoumon by probenecid. Its accelerated elimination may be a consequence of the increased formation of hydroxylated metabolites.

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. However, the elimination half-life was 6.0 h in controls and 9.5 h in cirrhotics. Antipyrine clearance was markedly decreased in patients with cirrhosis, but no correlation was found with the pharmacokinetic parameters of hydrolysed bopindolol. Although the AUC was not significantly altered in patients with cirrhosis, the longer half-life of hydrolysed bopindolol suggests impairment of its disposition in liver disease, which could lead to significant accumulation of drug during chronic dosing.

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. This conclusion can be drawn from the fact that phytohaemagglutinin (PHA) (0.4 microgram/well) and pokeweed mitogen (PWM) (0.4 microgram/well) induced lymphocyte proliferation were found to be significantly increased in comparison to pretreatment values on day 7 in both cimetidine regimens (800 mg; PHA: mean proliferation 66,500 before treatment to 166,00 cpm, PWM: mean proliferation 8,800 before treatment to 34,000 cpm; 1,600 mg; PHA; mean proliferation 48,700 before treatment to 81,600 cpm; PWM: mean proliferation 6,300 before treatment to 16,200 cpm). Increased mitogen-induced proliferation following cimetidine intake is of special interest because the mechanisms of this activation process are incompletely known. Lymphocyte proliferation response is dependent on the availability of extracellular calcium. The function of the other bivalent cations is unknown. We found that the extent of mitogen-induced lymphocyte proliferation correlates with cellular intralymphocytic zinc and magnesium amounts (coefficients of correlation [r]) (800 mg: PHA/Mg r = 0.84; PHA/Zn r = 0.86; PWM/Mg r = 0.88; PWM/Zn r = 0.87). Though the application of both cimetidine doses causes enhanced mitogen-induced lymphocyte proliferation on day 7, T lymphocytes with different phenotypic properties appear to be influenced by cimetidine. In the first dose regimen (800 mg) the number of the CD8 lymphocytes decreased significantly from 16.1% (365 cell/microliters blood) to 12.7% (264 cells/microliters blood) after 7 d of cimetidine intake. After the period of high-dose (1,600 mg) cimetidine administration (at day 21) numbers of CD4 lymphocytes were significantly increased from 41.5% (860 cells/microliters blood) to 56.3% (1,210 cells/microliters blood). Our results show that although different cimetidine doses obviously influence different cell types of healthy volunteers, the cellular mechanisms are the same, namely, a proliferation and an increased incorporation of magnesium and zinc in lymphocytes.

[Probenecid affects liver metabolism]. / Probenecid beeinflusst den Lebermetabolismus.

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. Plasma protein-C-antigen concentrations following intravenous PPC were significantly increased by probenecid. The plasma half-life of antipyrine after 7 days of probenecid therapy was significantly diminished. Accordingly, urinary excretion of 6 beta-hydroxycortisol was significantly increased. These data appear for the first time to reveal enzyme-inducing properties of probenecid, which may be responsible for the shortening of PPC plasma half-life when probenecid is given simultaneously. In addition, the influence of probenecid on plasma protein-C-antigen concentrations may indicate further effects of probenecid on liver metabolism.

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. The in vitro lymphocyte proliferation response to plant mitogens was increased. In contrast to results obtained from a previous study with healthy volunteers who were given 800 mg cimetidine, we found no significant increase in the CD4/CD8 ratio and no decrease in the CD8 but a significant increase in the CD4 cell count. Whereas the peripheral blood immune system showed signs of immune system activation following 800 and 1,600 mg cimetidine intake, reactivity patterns of skin immune system, however, differed in both studies. The data suggests that cimetidine has a dose and time dependent effect on the immune system.

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. Coadministration of famotidine and nifedipine, however, led to a significant increase of these parameters. In an additional double-blind study, a significant rise of the preejection period and of the ratio was detected after administration of famotidine alone. In impedance cardiography stroke volume and cardiac output were significantly reduced by famotidine. Heart rate and blood pressure values were not altered by the H2-antagonist. For the first time, to our knowledge, the observed changes of hemodynamic parameters appear to indicate that famotidine may exert negative effects on cardiac performance which, in our opinion, could be of clinical relevance in elderly subjects or in patients with heart failure.

Effect of aminophylline on cisplatin nephrotoxicity in the rat.

1. The effect of the methylxanthine aminophylline on cisplatin (5 mg kg-1 i.v.)-induced acute renal failure was investigated in the rat. Renal function was measured 5 days after cisplatin administration. 2. Cisplatin caused a polyuric acute renal failure. The creatinine clearance was significantly reduced. 3. Aminophylline (24 mg kg-1 12h-1) ameliorated the cisplatin nephrotoxicity when administered during the maintenance phase of acute tubular necrosis. However, it had no effect when only administered prophylactically before the cisplatin application. 4. Enprofylline (20 mg kg-1 4h-1 with dose adjustment), a methylxanthine lacking adenosine receptor antagonism in comparison to aminophylline, had no protective effect on cisplatin nephrotoxicity. 5. Adenosine is a renal vasoconstrictor and decreases glomerular filtration rate. Endogenous adenosine in the kidney is formed by degradation of ATP and is thought to be involved in various forms of acute renal failure. The results suggest that adenosine may be involved in the haemodynamic changes in the kidney induced by cisplatin.

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. Each period lasted for 7 d. Felodipine ER did not alter the pharmacokinetics of digoxin when given as a single dose or at steady state compared with placebo. At steady state the felodipine plain tablet resulted in an 11% increase (P less than 0.05) in peak plasma concentrations of digoxin. Systolic time intervals as noninvasively measured haemodynamic parameters were not significantly altered following the felodipine ER period, while the felodipine plain tablet significantly decreased the pre-ejection/left ventricular ejection time ratio compared to placebo.

[Mechano- and impedance cardiography parameters in patients with heart failure in administration of a calcium antagonist. The significance of the Heather index]. / Mechano- und impedanzkardiographische Parameter bei Patienten mit Herzinsuffizienz unter Gabe eines Kalziumantagonisten. Die Bedeutung des 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). In ICG the Heather-index proved to be a more reliable parameter of left ventricular function than the calculation of stroke volume and cardiac output, respectively. This is probably due to the fact that the distance between the electrode (L) is not considered for the Heather-index, while it has to be taken into account for determining stroke volume and cardiac output. When performing impedance cardiography in the elderly, the distance between the electrodes may be a source of error because of a lack of cooperation, possible underlying corpulance, or due to a restricted motility of the chest or the vertebral column. In these patients the Heather-index should be preferred to the calculation of stroke volume and cardiac output, whereas in healthy subjects the latter parameters seem to be of sufficient validity.