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Biomedical subjects

G Mikus

Publications and source records attributed to G Mikus.

At least 55 records · Page 3Linked to original sources
PubMed1992

Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

1. The pharmacokinetics, protein binding, bioavailability and metabolism of (+)-R- and (-)-S-nitrendipine were studied in six healthy subjects following random oral administration of 20 mg (+)-R-, 20 mg (-)-S- and 20 mg R,S-nitrendipine (pseudoracemic mixture of 10 mg [13C4)-(+)-R- and 10 mg (-)-S-enantiomer). 2. After administration of the enantiomers pronounced differences in AUC (R: 29.9 +/- 20.1; S: 123.8 +/- 63.7 ng ml-1 h; P less than 0.05), bioavailability (R: 10.7 +/- 7.4%; S: 44.6 +/- 23.1%; P less than 0.05) and Cmax (R: 14.4 +/- 7.7; S: 72.5 +/- 40.5 ng ml-1; P less than 0.05) were observed between R- and S-nitrendipine. When racemic nitrendipine was given bioavailability and dose normalized AUC and Cmax values of the S-enantiomer were not different from the values after S-nitrendipine-administration. In contrast, bioavailability (R: 10.7% R,S: 22.1%) and dose normalized AUC (R: 15.0; R,S: 29.5 ng ml-1 h and Cmax (R: 7.2; R,S: 16.8 ng ml-1) of R-nitrendipine were doubled following R,S- as compared with R-nitrendipine administration. t1/2 (R: 9.8; S: 9.1 h) and tmax were not different between the enantiomers nor were the values different after administration of the enantiomers or racemate. The fraction unbound in serum of R-nitrendipine was 0.0098 +/- 0.0032 (s.d.) and that of S-nitrendipine was 0.0083 +/- 0.0015 (s.d.). 3. The AUC values of the major pyridine metabolite M1 were similar after administration of R- and S-nitrendipine (S: 114.7 +/- 48.5; R: 71.7 +/- 29.9 ng ml-1 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Codeine O-demethylation: rat strain differences and the effects of inhibitors.

The oxidative metabolism of more than 20 drugs (e.g. sparteine, debrisoquine, dextromethorphan) is mediated by cytochrome P450IID6. Codeine O-demethylation to morphine was recently demonstrated to co-segregate with the polymorphic metabolism of debrisoquine and dextromethorphan. The female Dark-Agouti rat (DA) is an animal model for the poor metabolizer phenotype (PM) using debrisoquine or dextromethorphan as substrates. Studies were carried out to evaluate codeine metabolism in liver microsomes from female DA and Sprague-Dawley (SD) rats. The intrinsic clearance of codeine to morphine was 10-fold lower in DA rats due to a 5-fold higher Km (287 vs 49 microM) and a 2-fold lower Vmax (48 vs 94 nmol/mg/hr). Nineteen drugs were tested for inhibition of codeine O-demethylation. The four most potent competitive inhibitors were dextromethorphan (Ki = 2.53 microM), propafenone (Ki = 0.58 microM), racemic methadone (Ki = 0.3 microM) and quinine (Ki = 0.07 microM). The differences in morphine formation from codeine between SD and DA rats and the inhibition results show that this animal model appears to be a suitable model for the human EM and PM phenotypes, respectively. These strains could be used to study the pharmacodynamic consequences of the genetic polymorphism in codeine O-demethylation, and the effects of metabolic inhibitors. The outcome of these studies could impact on the therapy of pain control.

Animals↗
PubMed1991

Acute haemodynamic effects of i.v. nitrendipine in healthy subjects.

The haemodynamic effects of an i.v. infusion of 2 mg nitrendipine have been studied in six healthy volunteers. Nitrendipine significantly decreased the systolic (-8.3%) diastolic (-19.9%) and mean arterial (-11.6%) blood pressures and the peripheral vascular resistance (-57.8%), and significantly increased leg blood flow (+128%). Stroke volume did not change. Due to the increase in heart rate (+28.5%), the cardiac output (2.8.2%) rose significantly. The haemodynamic effects were closely related to the serum nitrendipine concentration. The sigmoidal Emax-model was appropriate to describe the data. Pronounced interindividual differences in the serum nitrendipine concentrations required to elicit 50% of the maximum haemodynamic effect (EC50) were observed. The EC50 for the increase in leg blood flow ranged from 2.9 to 30.9 ng/ml and for the reduction in peripheral vascular resistance from 2.1 to 25.7 ng/ml. Interindividual differences in EC50 values were less pronounced if based on unbound serum nitrendipine levels. The fraction of nitrendipine not bound to serum proteins showed a three-fold difference between subjects, with free fractions ranging from 0.011 to 0.036. The unbound EC50 values for the increase in leg blood flow varied between 0.06 and 0.44 ng/ml and for the reduction in peripheral vascular resistance from 0.07 to 0.35 ng/ml. Based on the serum concentrations associated with comparable haemodynamic effects nitrendipine was at least three-times more potent than nifedipine.

Adult↗
PubMed1991

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH.

The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml.min-1; S 379 ml.min-1) than in EMs (R 783 ml.min-1; S 828 ml.min-1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml.min-1; S 201 ml.min-1) relative to extensive metabolisers (R 533 ml.min-1; S 586 ml.min-1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml.min-1) than extensive (267 ml.min-1) metabolisers. The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng.ml-1 would not be attained in the PMs studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pharmacokinetics, bioavailability, metabolism and acute and chronic antihypertensive effects of nitrendipine in patients with chronic renal failure and moderate to severe hypertension.

1. The pharmacokinetics, bioavailability, metabolism and antihypertensive effects of nitrendipine have been studied in 12 patients with impaired renal function and moderate to severe hypertension. The drug was administered simultaneously by the i.v. [13C4] and oral (commercial tablet 20 mg) routes. 2. No differences in the pharmacokinetic parameters were observed between the two routes of administration. The systemic clearance after i.v. administration in patients with renal impairment (18.2 +/- 6.1 ml min-1 kg-1) was similar to that observed in healthy volunteers. Despite complete absorption of drug from the tablet the bioavailability of the parent compound was 21.2 +/- 12.5%. Cumulative urinary excretion of nitrendipine metabolites was correlated with the creatinine clearance (r = 0.946). 3. Significant reductions in mean arterial blood pressure (mean: 23.6%) at the end of the nitrendipine infusion and after oral administration of 20 mg (mean: 17.5%) were observed. The blood pressure lowering effect of nitrendipine could be correlated within individuals with serum nitrendipine concentrations using a log linear model. 4. Following 4 weeks of therapy an average dose of 77 mg nitrendipine day-1 was required to achieve a systolic blood pressure below 160 mm Hg or a diastolic blood pressure below 90 mm Hg. The reduction in blood pressure during multiple dosing was related to the nitrendipine steady-state concentration. There was a significant relationship between the nitrendipine bioavailability and the dose required for sufficient blood pressure control. 5. No accumulation of nitrendipine caused by impaired renal function was observed during multiple dosing. Thus, no reduction of the nitrendipine dose in patients with renal impairment is necessary.

Adult↗
PubMed1991

Thebaine O-demethylation to oripavine: genetic differences between two rat strains.

1. Codeine O-demethylation to morphine is mediated by cytochrome P450 IID1 (rat), or P450 IID6 (man), and exhibits genetic polymorphism. Thebaine is a precursor in the formation of endogenous morphine and codeine in man, being O-demethylated to oripavine. 2. The objective of the present study was to ascertain whether the O-demethylation of thebaine to oripavine was mediated by cytochrome P450 IID1 in rat liver microsomes. 3. Thebaine O-demethylation showed strain differences in female Sprague-Dawley (SD) and female Dark-Agouti (DA) rats, which serve as a model for the human debrisoquine/sparteine metabolism phenotypes. 4. The total intrinsic clearance of thebaine to oripavine was high (19.7 ml/h per mg protein) in SD rats, indicating that oripavine is a major metabolite of thebaine. A 3-fold lower intrinsic clearance was observed in DA rats (6.7 ml/h per mg protein). 5. Thebaine O-demethylation was inhibited by quinine and known substrates of cytochrome P450 IID1/P450 IID6, supporting the major involvement of cytochrome P450 IID1 in oripavine formation in rats.

Animals↗
PubMed1991

Polymorphic metabolism of opioid narcotic drugs: possible clinical implications.

The oxidative metabolism of many drugs is under genetic control. The enzyme responsible for this reaction for this group of drugs is cytochrome P-450IID6. Humans can be classified either as extensive metabolisers or, if lacking this enzyme, poor metabolisers. The incidence of poor metabolisers in caucasian subjects is 7-10%. The hepatic O-demethylation of codeine to morphine, quantitatively a minor metabolic process, represents this type of genetic polymorphism and has been studied in human pharmacokinetic studies, human urinary recovery studies, and in human and rat liver microsome experiments. Based on the current understanding that the analgesic effect of codeine is mediated primarily through morphine, one might anticipate that poor metabolisers would not obtain pain relief from codeine. The clinical significance of this polymorphism to the antidiarrhoeal and antitussive properties of codeine is not known. Others opioids (dihydrocodeine, hydrocodone, oxycodone, and thebaine) are structurally similar to codeine and their metabolism (O-demethylation at the 3 position) might also be under genetic control. Pharmacogenetics may play an important role in explaining the wide variability of the clinical response to many opioid drugs.

Alfentanil↗
PubMed1990

Dopamine infusion in healthy subjects and critically ill patients.

1. Little is known about the metabolism and the pharmacokinetics of dopamine (DA) in critically ill patients. To study the influence of the total administered DA dose on the disposition of free (i.e. unconjugated) and sulfoconjugated DA, plasma levels of free and sulfoconjugated DA were measured following infusion of 5 micrograms DA/kg per min for 0.5 and 3 h in six healthy volunteers and in eight critically ill patients receiving DA at the same infusion rate for 6.5 to 329 h. 2. In patients and volunteers steady state concentrations of free DA showing fairly large inter-individual variations (12.4-73.4 micrograms/L) were reached within 10 min of the beginning of the infusion. 3. DA sulfate was generated immediately. In volunteers peak values of the sulfoconjugate were observed 15-60 min after the termination of the DA infusion. In patients steady state concentrations of conjugated DA (63-80 micrograms/L) were reached within 5-10 h of DA infusion. 4. The initial half-life (t1/2 alpha), the terminal elimination half life (t1/2) and the distribution volume of free DA in the volunteers were significantly higher after 3 h of the DA infusion as compared to the shorter infusion. These parameters as well as the total plasma clearance of free DA were independent of the length of the DA infusion period in patients. The large distribution volumes of 19.8-75 L/kg indicate that DA has been taken up by peripheral tissues. 5. Substantial inter-individual variations in the patients' clearance of free DA (3.9-16.5 L/kg per h) may partly explain the variability in haemodynamic responses to DA infusion reported in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Interaction of verapamil and cimetidine: stereochemical aspects of drug metabolism, drug disposition and drug action.

The pharmacokinetics, metabolism and pharmacodynamics of verapamil (160 mg p.o. of a pseudoracemic mixture) were evaluated in six healthy volunteers before and after coadministration of cimetidine (400 mg b.i.d.). Enantiomers of verapamil and enantiomers of three major urinary metabolites (norverapamil, D-617 and D-620) were determined in plasma and urine by gas chromatography-mass spectrometry. Coadministration of cimetidine led to a significant increase in the area under the plasma concentration vs. time curve of S-verapamil (29.2 +/- 31.8 min x nmol x ml-1 vs. 41.2 +/- 33.7 min x nmol x ml-1; P less than .003) and R-verapamil (124.7 +/- 112.2 min x nmol x ml-1 vs. 156.8 +/- 105.0 min x nmol x ml-1; P less than .01). The increase was significantly greater for the pharmacologically more potent S-enantiomer compared to R-verapamil (150.3 +/- 37 vs. 117.8 +/- 15%; P less than .05). As a consequence, coadministration of cimetidine increased the negative dromotropic effect of verapamil on atrioventricular conduction in five of six subjects. In addition, fractional metabolic clearance to D-620 and D-617 decreased for both enantiomers. Tubular secretion of S-D-617 was inhibited by cimetidine (342 +/- 104 vs. 238 +/- 52 ml x min-1; P less than .05) whereas secretion of the R-enantiomer remained unchanged (276 +/- 91 vs. 222 +/- 43 ml x min-1). Thus, cimetidine interacts with both hepatic and renal verapamil elimination in a stereoselective manner. The increase in total plasma concentration of verapamil combined with an increase in eutomer/distomer ratio produces a more pronounced pharmacological effect of verapamil when cimetidine is coadministered.

Administration, Oral↗
PubMed1989

In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone.

Propafenone is a new class 1 antiarrhythmic agent. The drug is extensively metabolized. 5-Hydroxylation and N-dealkylation constitute major metabolic pathways. Recently it has been demonstrated that the in vivo metabolism of propafenone is controlled by the debrisoquin/sparteine polymorphism. To elucidate which of the above metabolic reactions is catalyzed by cytochrome P-450db1, the formation of 5-hydroxypropafenone and N-desalkylpropafenone was studied in the microsomal fraction of four human kidney donor livers previously characterized with regard to their ability to hydroxylate the beta-adrenergic antagonist bufuralol. The l'hydroxylation of bufuralol is catalyzed by the P-450db1 responsible for polymorphic debrisoquin/sparteine oxidation. The formation of 5-hydroxypropafenone but not N-desalkylpropafenone was closely related to bufuralol l'hydroxylation. Incubation with LKM1 antibodies, which selectively recognize P-450db1, inhibited 5-hydroxypropafenone formation completely whereas N-dealkylation was unimpaired. Propafenone was a strong competitive inhibitor of bufuralol l'hydroxylation. Thus it can be concluded that 5-hydroxypropafenone is formed by the cytochrome P-450 isozyme involved in polymorphic bufuralol oxidation.

Autoantibodies↗
PubMed1989

The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide.

The pharmacokinetics and urinary excretion of flecainide (50 mg administered orally) were investigated in five extensive metabolizers (EMs) and five poor metabolizers (PMs) of the sparteine/debrisoquin type of polymorphism under conditions of controlled urinary pH. Flecainide disposition was altered in the PMs. The AUC was higher (1462 +/- 407 versus 860 +/- 256 hr ng/ml), the elimination half-life prolonged (11.8 versus 6.8 hours), and the amount excreted in the urine was higher (26.7 +/- 7.2 versus 15.4 +/- 1.3 mg) in PMs compared with EMs (p less than 0.05). Oral clearance of flecainide was reduced (p less than 0.019) in PMs (600 +/- 139 versus 1041 +/- 307 ml/min in EMs). The renal clearance was similar (p greater than 0.05) in PMs (308 +/- 70 ml/min) and EMs (315 +/- 69 ml/min) and, consequently, PMs had a lower (p less than 0.008) metabolic clearance of flecainide (292 +/- 136 versus 726 +/- 240 ml/min in EMs). Under conditions of uncontrolled urinary flow and pH, renal excretion of flecainide will be reduced and the difference in disposition will be greater. In PMs with renal impairment, accumulation of flecainide to very high serum concentrations may be anticipated, and this may result in proarrhythmic effects.

Adult↗
PubMed1989

Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.

1. The disposition of the enantiomers of the antiarrhythmic drug flecainide has been studied in five extensive (EM) and five poor (PM) metabolisers of sparteine/debrisoquine after administration of 50 mg of racemic flecainide acetate under conditions of high urinary flow rate and acidic urinary pH. 2. In the EM subjects there were no significant differences in the oral clearance, half-life or urinary excretion of (+)-S- and (-)-R-flecainide. 3. In the PM subjects differences in the pharmacokinetics of S- and R-flecainide were observed. The oral clearance of R-flecainide (467 +/- 109 ml min-1) was less (P less than 0.03) than that of the S-enantiomer (620 +/- 172 ml min-1). The half-life of R-flecainide (12.9 h) was longer (P less than 0.03) than that of S-flecainide (9.8 h). The renal clearance of the two enantiomers was, however, comparable and similar to that observed in the EM subjects. The urinary recovery of R-flecainide (15.6 +/- 3.7 mg) was greater (P less than 0.03) than that of the S-enantiomer (12.0 +/- 3.7 mg). The enantioselective disposition observed in PMs is therefore due to greater impairment in the metabolism of R- than S-flecainide. 4. The urinary recoveries of two major metabolites of flecainide, meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) were lower (P less than 0.05) in PMs, 12.0% +/- 3.1% and 8.2% +/- 3.2% of the dose administered, respectively, than in EMs of 17.7% +/- 3.3% and 16.5% +/- 3.3%, respectively. 5. One PM subject had a greatly diminished flecainide metabolic capacity and a rare genotype, as assigned by Xbal RFLP analysis.

Debrisoquin↗
PubMed1988

Pharmacokinetics and pharmacodynamics of nitrendipine in healthy subjects and patients with kidney and liver disease.

Nitrendipine [3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate] is a calcium antagonist with a dihydropyridine structure that has a great structural resemblance to nifedipine. Instead of a methyl group in position 3, it has an ethyl group and the NO2 group is in the meta instead of in the ortho position. These minor structural differences have a pronounced impact with respect to both the pharmacokinetics and pharmacodynamics of nitrendipine as compared to nifedipine. Based on equimolar plasma concentrations, nitrendipine is on average three times more potent than nifedipine with regard to the reduction of peripheral vascular resistance, arterial blood pressure, and increased leg blood flow. The terminal half-life is on average 8 h, and thus substantially longer than the terminal half-life of 2-3 h for nifedipine. Despite its almost complete absorption, bioavailability is on average 15-25% and shows great interindividual variability ranging from 7 to 40%. The systemic plasma clearance of the drug is on average 18 ml/min/kg and thus approaches the liver blood flow. In patients with liver cirrhosis, the half-life is prolonged to 19.6 h, the total plasma clearance is decreased by 50%, and the bioavailability is more than doubled to 54%. No data are available if liver disease alters the pharmacodynamic response of the drug. Kidney disease has some effect on the disposition of the drug. Systemic clearance is not changed but the terminal elimination half-life is slightly prolonged to 10.5 h. This increase in half-life is due to an increased volume of distribution. Bioavailability, which is 21.2%, is not grossly altered in renal failure.

Humans↗
PubMed1987

Application of stable isotope methodology to study the pharmacokinetics, bioavailability and metabolism of nitrendipine after i.v. and p.o. administration.

1. The pharmacokinetics, bioavailability and metabolism of nitrendipine were studied in six healthy volunteers (three females, three males) using [13C4]-nitrendipine as a biological internal standard. In the first study the drug was administered simultaneously by the i.v. [13C4] and p.o. (solution) routes and in a second study two oral preparations (13C4-solution and commercial tablet) were administered, also simultaneously. 2. The mean terminal elimination half-life was 8.3 +/- 3.2 h (range 3.4 to 16 h) with no differences between the intravenous and oral route of administration. Total plasma clearance averaged 18.7 +/- 0.6 ml min-1 kg-1 and volume of distribution at steady state 5.4 +/- 2.4 1 kg-1. 3. Following oral administration of nitrendipine solution the percentage of dose absorbed was 88.4 +/- 16.0% based on urinary excretion of metabolites. Despite its almost complete absorption, absolute bioavailability of the solution was only 22.6 +/- 6.7% due to extensive presystemic elimination. The bioavailability of the commercial tablet relative to the solution was 82.2 +/- 20.3%. 4. Both after i.v. and oral administration the drug was extensively metabolized with less than 0.5% of the dose excreted as unchanged drug in urine. Cleavage of the two ester functions in position 3 and 5, respectively, to carboxylic acids and further hydroxylation of the methyl groups in position 2 and 6 of the pyridine ring to the corresponding hydroxymethyl carboxylic acids constituted the major urinary metabolites accounting for 35.0 +/- 16.5% (i.v.) and 32.8 +/- 20.4% (p.o.), respectively, of the dose administered. 5. Binding of nitrendipine to plasma proteins was high with a fraction unbound of only 0.02 +/- 0.012 (range 0.011 to 0.036).

Administration, Oral↗
PubMed1986

Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine.

The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thus, it is unlikely that quinidine metabolism is controlled by the sparteine/debrisoquine gene locus.

Adult↗
PubMed1986

Does the benzodiazepine antagonist Ro 15-1788 antagonize the action of ethanol?

Ethanol aggravates benzodiazepine-induced central nervous depression by pharmacokinetic and/or pharmacodynamic interactions and Ro 15-1788 reverses promptly the hypnotic effects of benzodiazepines. We therefore studied the acute effects of Ro 15-1788 on the ethanol-induced sedation in six healthy male subjects. Subsequently to an oral loading dose (0.54 g ethanol kg-1) ethanol was infused for 4 h (0.15 g ethanol kg-1 h-1) and steady state blood levels between 0.9 to 1.2 g l-1 were reached within 2 h. At steady state and during the elimination phase of ethanol an intravenous bolus of 0.5 mg Ro 15-1788 or placebo was administered in a randomized, double-blind crossover fashion. The marked sedative effects of ethanol as assessed by visual analogue scales (2 to 6 fold increase in the sedation index), and choice reaction time (25 to 40% prolongation) were not affected by Ro 15-1788. However, the pharmaco-EEG indicated that Ro 15-1788 seems to reverse transiently the ethanol-induced changes in total alpha, delta, and slow alpha bands. There was no pharmacokinetic interaction between both agents since elimination of Ro 15-1788 (t1/2 = 1.2 +/- 0.7 h) and of ethanol (0.17 +/- 0.02 g l-1 h-1) were in good agreement with control values. Thus, it could be concluded that Ro 15-1788 might affect for a short while the action of ethanol by interfering with the benzodiazepine receptors.

Adult↗