Search PubMed⌕ Search

Biomedical subjects

P Dayer

Publications and source records attributed to P Dayer.

At least 127 records · Page 7Linked to original sources
PubMed1986

The molecular mechanisms of two common polymorphisms of drug oxidation--evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation.

Using the stereospecific metabolism of (+)- and (-)-bufuralol and (+)- and (-)-metoprolol as model reactions, we have characterized the enzymic deficiency of the debrisoquine/sparteine-type polymorphism by comparing kinetic data of subjects in vivo with their microsomal activities in vitro and with reconstituted activities of cytochrome P-450 isozymes purified from human liver. The metabolism of bufuralol in liver microsomes of in vivo phenotyped 'poor metabolizers' of debrisoquine and/or sparteine is characterized by a marked increase in Km, a decrease in Vmax and a virtual loss of the stereoselectivity of the reaction. These parameters apparently allow the 'phenotyping' of microsomes in vitro. A structural model of the active site of a cytochrome P-450 for stereospecific metabolism of bufuralol and other polymorphically metabolized substrates was constructed. Two cytochrome P-450 isozymes, P-450 buf I and P-450 buf II, both with MW 50,000 Da, were purified from human liver on the basis of their ability to metabolize bufuralol to 1'-hydroxy-bufuralol. However, P-450 buf I metabolized bufuralol in a highly stereoselective fashion ((-)/(+) ratio 0.16) as compared to P-450 buf II (ratio 0.99) and had a markedly lower Km for bufuralol. Moreover, bufuralol 1'-hydroxylation by P-450 buf I was uniquely characterized by its extreme sensitivity to inhibition by quinidine. Antibodies against P-450 buf I and P-450 buf II inhibited bufuralol metabolism in microsomes and with the reconstituted enzymes. Immunochemical studies with these antibodies with microsomes and translations in vitro of RNA from livers of extensive and poor metabolizers showed no evidence for a decrease in the recognized protein or its mRNA. Because the antibodies do not discriminate between P-450 buf I and P-450 buf II, both a decreased content of P-450 buf I or its functional alteration could explain the polymorphic metabolism in microsomes. The genetically defective stereospecific metabolism of mephenytoin was determined in liver microsomes of extensive and poor metabolizers of mephenytoin phenotyped in vivo. Microsomes of poor metabolizers were characterized by an increased Km and a decreased Vmax for S-mephenytoin hydroxylation as compared to extensive metabolizers and a loss of stereospecificity for the hydroxylation of S-versus R-mephenytoin. A cytochrome P-450 with high activity for mephenytoin 4-hydroxylation was purified from human liver. Immunochemical studies with inhibitory antibodies against this isozyme suggest the presence in poor-metabolizer microsomes of a functionally altered enzyme.

Adrenergic beta-Antagonists↗
PubMed1986

Serum protein binding of diazepam and propranolol in the feto-maternal unit from early to late pregnancy.

Paired samples of maternal and fetal serum were obtained in 65 pregnancies between 13 and 41 weeks gestation. Concentrations of albumin, alpha 1-acid glycoprotein (alpha 1-AGP) and free fatty acids (FFA) were estimated in all samples and the in-vitro binding of diazepam and propranolol was estimated. The free fraction of diazepam in fetal serum was very high in early gestation and decreased with advancing gestation to reach maternal values around the 30th week. After 35 weeks gestation, values were generally lower in fetal than in maternal serum. Fetal serum binding of diazepam correlated with fetal albumin levels and gestational age. The ratio of the fetal/maternal free diazepam fraction correlated negatively with the fetal/maternal serum albumin concentration ratio. The maternal/fetal free diazepam fraction ratio correlated positively with gestational age. The free fraction of propranolol in fetal serum was higher than in maternal serum in early pregnancy and decreased with advancing gestation but always remained higher than the maternal values. The fetal/maternal free propranolol fraction ratio was negatively correlated with the fetal/maternal alpha 1-AGP serum concentration ratio. The maternal/fetal free propranolol fraction ratio was positively correlated with gestational age. Serum protein binding of propranolol was correlated with serum albumin concentrations in fetal samples but not in maternal samples. Serum FFA concentrations were not correlated with serum protein binding except for maternal serum binding of diazepam. For toxicological reasons it is advisable to monitor maternal blood for free concentrations of drugs that exhibit concentration-dependent protein binding or which can be displaced from binding sites by other drugs or endogenous compounds such as FFA.

Adolescent↗
PubMed1985

Effect of oxidative polymorphism (debrisoquine/sparteine type) on hepatic first-pass metabolism of bufuralol.

Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.

Adrenergic beta-Antagonists↗
PubMed1985

Interindividual variation of beta-adrenoceptor blocking drugs, plasma concentration and effect: influence of genetic status on behaviour of atenolol, bopindolol and metoprolol.

Ten healthy subjects whose genetic oxidative phenotype had been determined (6 extensive and 4 poor metabolizers of the debrisoquine-sparteine type of polymorphism) received single oral doses of 3 beta-blockers: atenolol, bopindolol and metoprolol. The plasma concentrations and the extent of the decrease in exercise-induced tachycardia were determined. The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol. The metabolic pathway under genetic control was highly stereoselective. This observation must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.

Adrenergic beta-Antagonists↗
PubMed1985

Mephenytoin hydroxylation polymorphism: characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo.

The rate of 4-hydroxylation and of N-demethylation of S- and R-mephenytoin was determined in liver microsomes of 13 extensive (EM) and two poor (PM) metabolizers of mephenytoin. Detailed kinetic studies were performed in microsomes of eight EMs and the two PMs. Microsomal mephenytoin metabolism in PMs was characterized by an increased Km (150.6 and 180.6 vs. a mean [+/- SD] 37.8 +/- 9.6 mumol/L S-mephenytoin in 8 EMs), a decreased maximum rate of metabolism for S-mephenytoin hydroxylation (0.76 and 0.69 vs 4.85 +/- 1.65 nmol 4-hydroxymephenytoin per milligram protein per hour), and loss of stereoselectivity for the hydroxylation of the R- and S-enantiomers of mephenytoin (R/S ratio: 1.10 and 0.76 vs. 0.11 +/- 0.04 in 13 EMs). The formation of 4-OH-mephenytoin from R-mephenytoin and the demethylation reaction remained unaffected. These results support our hypothesis that the mephenytoin polymorphism is caused by a partial or complete absence or inactivity of a cytochrome P-450 isozyme with high affinity for S-mephenytoin.

Adult↗
PubMed1984

Characterization of a common genetic defect of cytochrome P-450 function (debrisoquine-sparteine type polymorphism)--increased Michaelis is Constant (Km) and loss of stereoselectivity of bufuralol 1'-hydroxylation in poor metabolizers.

In order to define the mechanism of the debrisoquine-sparteine type genetic polymorphism of drug oxidation we studied the kinetics of bufuralol 1'-hydroxylation in liver microsomes from extensive and poor metabolizers and in a purified reconstituted human cytochrome P-450 isozyme with high activity for bufuralol 1'-hydroxylation, P-450[buf]. In extensive metabolizer microsomes the enzymatic reaction displayed apparent Michaelis-Menten kinetics and the (+)-isomer was preferentially metabolized. By contrast, the enzymatic reaction in poor metabolizer microsomes was characterized by a 4- to 5-fold increase in Km and by a loss of stereoselectivity. In a non-membraneous reconstituted system containing NADPH cytochrome P-450 reductase, a NADPH regenerating system and phospholipids, P-450[buf] exhibited an almost complete substrate stereoselectivity for (+)-isomer 1'-hydroxylation. It is concluded that the purified cytochrome P-450[buf] is the target of the debrisoquine-sparteine type oxidation polymorphism and that poor metabolizers have a quantitative or qualitative deficiency of this isozyme.

Cytochrome P-450 Enzyme System↗
PubMed1984

Debrisoquine-type polymorphism of drug oxidation: purification from human liver of a cytochrome P450 isozyme with high activity for bufuralol hydroxylation.

Indirect evidence suggests that the genetically defective metabolism of drugs such as debrisoquine and bufuralol observed in up to 10% of the population (poor metabolizers) is caused by the absence or functional deficiency of a cytochrome P450 isozyme. Using bufuralol-1'-hydroxylation to carbinol to optimize the procedure, 3 cytochrome P450 isozymes (P450A, P450buf, P450C) were purified to apparent electrophoretic homogeneity from human liver microsomes. P450buf had a specific activity of 20.3 nmol carbinol X nmol P450-1 X 15 min-1 as compared to microsomes (10.0 nmol carbinol X nmol P450(-1) X 15 min-1) when (+)-bufuralol was used as substrate. The stereoselective metabolism of (-)- and (+)-bufuralol to carbinol by purified P450buf [(-)/(+) ratio: 0.13] was strikingly different from that in the microsomes of either an extensive [(-)/(+) ratio: 0.4] or poor metabolizer [(-)/(+) ratio: 0.83] of bufuralol. We propose that this isozyme is the major bufuralol and debrisoquine hydroxylating species and is the target of the genetic deficiency.

Adrenergic beta-Antagonists↗
PubMed1984

Changes in serum albumin and alpha 1-acid glycoprotein concentrations during pregnancy: an analysis of fetal-maternal pairs.

The concentration of the two principal drug-binding proteins, albumin and alpha 1-acid glycoprotein, were measured in 44 paired fetal and maternal serum samples obtained at between 12 and 41 weeks gestation. Maternal serum albumin concentrations ranged between 25 and 35 g/l during this period. Fetal serum albumin was much lower in early gestation, ranging from 7.5 to 16 g/l at 12-15 weeks. With advancing age there was a linear increase so that at 30 weeks the fetal and the maternal serum albumin concentrations were in the same range and after 35 weeks the fetal concentrations exceeded the maternal by some 20%. Thus, the mean fetal/maternal serum concentration ratio of albumin increases from early pregnancy to term: 0.38 at 12-15 weeks; 0.66 at 16-25 weeks; 0.97 at 26-35 weeks; and 1.2 at greater than 35 weeks gestation. Maternal serum alpha 1-acid glycoprotein concentrations were scattered widely between 0.38 and 1.05 g/l. With the technique used fetal serum concentrations were hardly detectable before 16 weeks. Thereafter they increased at a constant rate, but never attained the maternal values. Near term a fetal/maternal serum concentration ratio of 0.37 was reached. These changes in protein concentrations may have important pharmacological implications.

Adolescent↗
PubMed1984

The effects of biliary obstruction on excretion of cefoperazone in the rat.

A study has been carried out on the influence of biliary obstruction on the elimination of cefoperazone (CPZ), an antibiotic mainly excreted in the bile. Rats were submitted to ligature of the common bile duct, given CPZ 100 mg/kg i.m., and killed 1 to 72 h afterwards. At death, measurements were made of CPZ concentrations in the serum, liver, lung, striated muscle, kidney, urine, intestinal wall and intestinal contents. The results were compared with those found in intact and in sham operated rats. Biliary obstruction led to a prolongation of the time taken for CPZ to disappear from the serum and markedly changed the way in which the drug was excreted. The amount of the drug excreted in the urine was 88% in the presence of biliary obstruction compared with 6% in intact rats and 14% in sham operated rats. The amount of CPZ in the small intestine 1 h after injection was very high in sham operated rats but only minimal amounts were found at this time in the presence of biliary obstruction. However, from 6 h after the injection, large amounts of CPZ were found in the intestinal contents despite the presence of biliary obstruction. In conclusion, in the presence of biliary obstruction, CPZ is eliminated by a combination of urinary and intestinal (non-biliary) excretion.

Animals↗
PubMed1983

[Effect of various types of liver diseases on the behavior of cefoperazone].

Cefoperazone is a third generation cephalosporin mainly excreted by the biliary route. Hepatic dysfunction may have a pronounced effect on its pharmacokinetic behaviour. Sixty liver patients (acute viral hepatitis, alcoholic fatty liver and liver cirrhosis), without overt renal disease, have been studied and compared to controls. In liver disease the total clearance of cefoperazone is markedly decreased by reduction of extrarenal clearance, which is variable for each type of liver injury. Renal clearance does not change or may even increase, when hypoalbuminemia is present and compensates the reduction in extrarenal clearance.

Adult↗
PubMed1983

[Quantitative approach to drug compliance of diabetics].

Many patients do not take their medication according to the instructions of their physician. Patient compliance is particularly poor in the long-term treatment of diseases, which produce only minor symptoms in the patient. The aim of the present study was to quantitate patient compliance in diabetics treated with tolbutamide. The amount of tolbutamide taken by the patient was estimated on the basis of its 24 hours urinary excretion. The collection of the 24 hours urine is a standard procedure in our outpatient clinic for the measurement of glycosuria. The study involved 33 diabetics followed over several months. In those reliable patients, who conscientiously took their medication, we found a good correlation between the prescribed dose and the 24 hours urinary excretion. In contrast, when the data from the entire group of 33 out-patients was evaluated, the correlation between these two parameters of prescribed dose and urinary excretion was poor. The correlation between urinary excretion and the dose admitted by the patient was just as poor. According to our results, only one out of two diabetics took the prescribed dose. After our initial observations, we informed the outpatients about their inclusion in this study. In spite of the fact that the patients knew that they were under observation for compliance, we found large interindividual differences in the urinary excretion of tolbutamide over several months. In contrast, the intraindividual variability was low. We found that interviews with patients are a poor means to detect non-compliance, whereas urinary excretion measurements appear to be more reliable.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus↗
PubMed1983

[Pharmacokinetic and clinical consequences of the genetic polymorphism of oxidation].

Bufuralol is a beta-adrenoceptor blocking drug whose metabolism is under the same genetic control as debrisoquine. Bufuralol appears to be a sensitive tool for characterization of this pharmacogenetic variation. After test drug absorption, one single blood collection allows separation between extensive and poor metabolizers. In Switzerland, the poor metabolizer status has a prevalence of 8%. In poor metabolizers bufuralol plasma concentrations are very high, an observation of interest when considering the occurrence of side effects of the drug. In addition to disease-induced variability in drug response, oxidation polymorphism is a major source of interindividual variations in drug effect. As the metabolism of numerous drugs is affected by this pharmacogenetic variation, the question arises whether systematic screening should not be considered.

Adrenergic beta-Antagonists↗
PubMed1983

Contribution of the genetic status of oxidative metabolism to variability in the plasma concentrations of beta-adrenoceptor blocking agents.

The oxidative metabolism of bufuralol is under the same genetic control as that of debrisoquine and sparteine. 154 fasting volunteers received a 30 mg tablet of bufuralol and a blood sample was taken 3 h later. In poor metabolizers (8% of the sample) the plasma bufuralol concentrations were very high and the metabolite concentrations were low. The genetic oxidative status is a major source of interindividual variation in the plasma concentration of drugs that undergo oxidative metabolism.

Adrenergic beta-Antagonists↗
PubMed1983

The genetic control of drug oxidation in the liver.

Hepatic drug oxidation is a major source of interindividual variations in drug behaviour. A wide spread of the pharmacokinetic parameters of extensively oxidized drugs is a common observation. For such compounds, in the absence of polymodal distribution of the kinetic parameters, no distinct genetic influence can be detected. The discovery that the urinary excretion of debrisoquine and its main hydroxylated metabolite displays a bimodal pattern opened a new field in the study of hepatic metabolism. This new genetic polymorphism now concerns the oxidative metabolism of numerous substances such as antihypertensive agents, antidepressants, antiarrhythmic drugs and various other unrelated compounds. The poor metabolizer phenotype is observed in some 8% of individuals in European populations. We have shown that the oxidative metabolism of beta-adrenoceptor blocking drugs is under the same genetic control as debrisoquine. Using bufuralol as a test drug, we have studied the influence of polymorphic oxidation on interindividual variations of parent drug and metabolite plasma concentrations. It appears clearly that oxidation polymorphism is a major factor of variability in hepatic drug handling. This fact has important clinical and pharmaceutical implications.

Adrenergic beta-Antagonists↗
PubMed1983

Consequences of renal insufficiency on the hepatic clearance of some drugs.

There have been numerous investigations into the effect of kidney or liver diseases on the renal or hepatic elimination of drugs, but little is known about the possible consequences of renal insufficiency on the hepatic clearance of medicinal agents. The first reports of diminished presystemic elimination of drugs in renal failure were presented by Bianchetti in 1976 for propranolol and by Levy in 1979 for dextropropoxyphene. We confirmed the fact that the hepatic presystemic elimination of drugs might be diminished by kidney diseases. We studied this phenomenon with the beta-blocking agents tolamolol, bufuralol and oxprenolol. Tolamolol is eliminated from the body mainly by aromatic hydroxylation and, for bufuralol, aliphatic hydroxylation also plays an important role, whereas, for oxprenolol, glucuroconjugation of the unchanged compound is an important route of elimination. After oral administration, the areas under the plasma/blood concentration curves were markedly increased in patients with renal insufficiency as compared to healthy subjects. The clearance approach of Rowland and Tozer led to the conclusion that decrease of the presystemic hepatic elimination might be the main reason for this finding. Cefoperazone is a cephalosporin eliminated to 75% by the biliary route under normal conditions. In a study in which the drug was intravenously infused to both healthy volunteers and patients with renal insufficiency, we found that in some patients the extrarenal clearance was markedly reduced. It is probable that in this situation the patients also suffered from a slight hepatic insufficiency, as sometimes observed in the case of kidney disease associated with a poor physical condition. It is well-known that in patients with terminal liver failure, the kidney may also be involved, producing a condition known as the "hepato-renal" syndrome. We feel that there is evidence to support the hypothesis that renal failure can disturb the pharmacokinetics of drugs by processes other than merely reducing their renal excretion. The precise causes of the decreased hepatic elimination found in renal patients remains, however, to be determined.

Adrenergic beta-Antagonists↗