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Biomedical subjects

T Walle

Publications and source records attributed to T Walle.

At least 73 records · Page 4Linked to original sources
PubMed1990

Stereoselective sulphate conjugation of racemic terbutaline by human liver cytosol.

1. The enantioselectivity of the sulphation of racemic terbutaline by phenolsulphotransferases was examined in vitro using cytosol from human livers (n = 3) and [35S]-3'-phosphoadenosine-5'-phosphosulphate (PAP35S) as the sulphate donor. 2. The radioactive sulphate conjugate formed was isolated by h.p.l.c. and its enantiomers were separated intact by h.p.l.c. after chiral derivatization. 3. Sulphation of racemic terbutaline occurred with the same apparent Km value for both enantiomers (270 microM). The extent of sulphation of the (+)-enantiomer was double that of the (-)-enantiomer, solely due to a difference in their apparent Vmax values. 4. Sulphation of racemic prenalterol, a structural analogue of terbutaline, also showed a two-fold preference for the (+)-enantiomer. 5. These findings suggest that enantioselective sulphate conjugation of chiral phenolic sympathomimetic amine drugs may lead to enantioselective pharmacokinetics that should be considered in the clinical use of these drugs.

Adolescent↗
PubMed1990

Pharmacokinetics and metabolism of oral doses of a 4'-methylthio derivative of propranolol in man.

1. The objective of this study was to determine the oral dose pharmacokinetics and metabolism of 4'-methylthiopropranolol (MTP) in man and compare the results with observations for propranolol in previous studies. 2. Three women and five men received single oral doses of MTP, dose range 5-320 mg. Plasma concentration of MTP over time were measured by gas chromatography-mass spectrometry. MTP metabolites in urine were identified by comparative high-performance liquid chromatographic (HPLC) retention times and mass spectrometry with previously characterized reference compounds and quantified by HPLC. 3. The oral clearance of MTP of 1.2-1.4 l/min for the 80, 160 and 320 mg doses was about one third of the value previously reported for propranolol. The half-life for MTP (3.3-4.1 h) was, however, similar to that of propranolol. In contrast to propranolol, the peak (2.5 h) plasma concentrations of MTP increased linearly with dose (5-320 mg). 4. The oral clearance for MTP was about 2-fold higher in the men than in the women (P less than 0.01). In addition, the clearance of the (S)-enantiomer was about 30% higher than that of the (R)-enantiomer (P less than 0.05), which was a reversal of that seen with propranolol. 5. The metabolism of MTP resulted mainly in sulphur oxidation to sulphoxide and sulphone metabolites. These two metabolites accounted for 75% of the MTP dose. This switching from aromatic carbon oxidation for propranolol to sulphur oxidation for MTP is proposed as the basis of the lower oral clearance of MTP. 6. This study also demonstrated higher plasma binding of MTP (unbound fraction 3.7%) than of propranolol (10.5%; P less than 0.01), a factor probably contributing to decreased tissue distribution of MTP.

Administration, Oral↗
PubMed1990

Chronic treatment with propranolol enhances the synthesis of prostaglandins E2 and I2 by the aorta of spontaneously hypertensive rats.

The effects of treatment with dl, d- or l-propranolol (subcutaneously for 1 week) on arterial blood pressure and on 6-keto prostaglandin (PG) F1 alpha (stable metabolite of PGI2) and PGE2 production by aorta, renal medulla and renal cortex were examined in spontaneously hypertensive rats. dl-Propranolol and l-propranolol significantly (P less than .05) lowered blood pressures from 148 +/- 9/113 +/- 5 (n = 6) and 133 +/- 4/100 +/- 2 (n = 12) mm Hg to 112 +/- 3/80 +/- 3 and 121 +/- 3/81 +/- 3 mm Hg, respectively. Comparable treatment of spontaneously hypertensive rats with inactive d-propranolol was without effect. Basal immunoreactive (i) i6-keto-PGF1 alpha and iPGE2 production by isolated aorta, renal medulla and cortex was not different in vehicle compared to the dl-propranolol-treated rats. In contrast, norepinephrine (1 microM)-stimulated synthesis of i6-keto PGF1 alpha and iPGE2 by the aorta in the dl-propranolol-treated group was significantly (P less than .05) enhanced compared with the vehicle-treated group. Aortic i6-keto-PGF1 alpha and iPGE2 synthesis stimulated by norepinephrine in l-propranolol-treated rats was also significantly (P less than .05) higher than that observed in vehicle and d-propranolol-treated rats. dl-Propranolol treatment did not alter norepinephrine-stimulated renal cortical or medullary i6-keto-PGF1 alpha or iPGE2 synthesis. Indomethacin (5 mg/kg i.p.) given on the last 2 days of dl-propranolol treatment, significantly inhibited aortic i6-keto-PGF1 alpha and iPGE2 production and blunted the antihypertensive effect of dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Stereoselective sulfation of terbutaline by the rat liver cytosol: evaluation of experimental approaches.

Little is known about the stereochemistry of sulfation of chiral phenolic drugs. In this study we examined several in vitro approaches to this question, using (+)-, (-)-, or (+/-)-terbutaline as the substrate and the rat liver cytosol as the phenolsulfotransferase enzyme source. The cosubstrate PAPS was either generated by the cytosol from inorganic sulfate and ATP or added to the cytosol. The intact sulfate conjugates formed were determined by HPLC. Using the PAPS generating system, which is best suited for the production of relatively large quantities of sulfate conjugates, with the individual enantiomers as substrates, (T)-terbutaline was conjugated to a much greater extent than (-)-terbutaline; the (+)/(-)-enantiomer ratio was 7.3 +/- 0.3 (mean +/- SE). When (+/-)-terbutaline was the substrate and chiral derivatization was employed to separate the sulfate enantiomers formed, a similar (+)/(-)-enantiomer ratio of 7.9 +/- 0.2 was obtained. With PAP35S added to the cytosol, an approach best suited for kinetic studies, the substrate concentration dependence of sulfation could be determined. The Km app for this reaction was identical for (+)- and (-)-terbutaline. However, the Vmax app was 8.1 +/- 0.4 times greater for (+)-terbutaline. This study for the first time shows enantioselectivity in sulfation of a chiral phenolic drug. The experimental approaches used should be valuable for human studies of stereoselective sulfation of terbutaline and other chiral drugs.

Adenosine Triphosphate↗
PubMed1989

Stereochemistry of tissue distribution of racemic propranolol in the dog.

Only limited information is available on the stereochemistry of the in vivo distribution of beta-receptor-blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium-labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminal t1/2 of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10-fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50-fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)-vs. (-)-propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (-)-propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue or CSF distribution.

Animals↗
PubMed1989

Propranolol's metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities.

The relative contributions of the debrisoquin and mephenytoin isozymes of hepatic cytochrome P-450 to the stereoselective metabolism of propranolol have been studied in a panel of volunteers of known oxidative phenotypes. Six subjects were extensive metabolizers of both debrisoquin and mephenytoin (EM). Four subjects were poor metabolizers of debrisoquin but rapid for mephenytoin (PMD). Five subjects were poor metabolizers of mephenytoin but rapid for debrisoquin (PMM), and one individual had a deficiency for both test compounds (PMD/M). Partial metabolic clearances of each propranolol enantiomer to 4-hydroxypropranolol (4-OH-P), the sulfate, and glucuronide conjugates of 4-OH-P, naphthoxylactic acid (NLA) and propranolol glucuronide, were estimated after a single oral dose of racemic propranolol (80 mg). The partial metabolic clearance of both enantiomers to total 4-OH-P in the PMD group was 75% less than in the EM and PMM groups, indicating the contribution of the debrisoquin isozyme to this route of metabolism. The R/S ratios for the clearance to 4-OH-P were similar between EM and PMD (2.5 +/- 0.5 vs 2.5 +/- 0.4, respectively), implying that the different enzymes involved in ring hydroxylation (i.e., the debrisoquin isozyme and other hydroxylases) have similar stereoselective preferences. The partial metabolic clearance to NLA was 55% less in the PMM group than in the EM and PMD groups, indicating that S-mephenytoin 4-hydroxylase contributes to the metabolic conversion of propranolol to NLA. The R/S ratios for the clearance to NLA were close to unity in all groups. The partial metabolic clearance to propranolol glucuronide also did not exhibit stereoselectivity and was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aryl Hydrocarbon Hydroxylases↗
PubMed1989

Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects.

This study determined the total clearance of propranolol and the partial clearances through each of its three primary metabolic pathways after administration of an 80 mg single oral dose in 28 young, white subjects (13 women; 15 men). The oral clearance of propranolol was significantly higher (63%, p less than 0.02) in the men (65.7 +/- 7.7 ml/min/kg; mean +/- SE) than in the women (40.2 +/- 6.2 ml/min/kg). This sex difference was mainly attributable to a 137% higher clearance through the P-450-mediated side-chain oxidation in the men (p less than 0.001). There was also a 52% higher clearance through glucuronidation in the men (p less than 0.02). In contrast, the clearance through the P-450-mediated ring oxidation was not different between men and women. After administration of simultaneous intravenous doses of hexadeuterium-labeled drug (0.1 mg/kg) to 11 of the subjects, there were no differences between men and women in volume of distribution or half-life. Moreover, there were no sex differences in plasma and blood binding of propranolol. This study thus demonstrates that higher plasma levels of propranolol occur in women than in men after oral doses and suggests that some drug metabolizing enzymes, but not others, are regulated by sex hormones in human beings.

Administration, Oral↗
PubMed1989

Stereoselective sulfation of R,S-4'-hydroxypropranolol by canine hepatic cytosol and partially purified phenolsulfotransferases.

The stereoselective formation of 4'-hydroxypropranolol sulfate (HOPS) from racemic 4'-hydroxypropranolol (HOP) has been investigated using canine hepatic cytosol and partially purified phenolsulfotransferases (PSTs). Pseudo first order rate constants, Vmax/Kmapp, were significantly greater (P less than .05) for the formation of R-HOPS by canine hepatic cytosol, S/R-HOPS = 0.72. Moreover, double reciprocal replots for the sulfation of both HOP enantiomers were biphasic, suggesting the presence of multiple PST enzymes. Pentachlorophenol (PCP) inhibited the sulfation of both HOP enantiomers with an IC50 of 244 nM, suggesting that phenol (P) forms of the PST enzymes may be primarily responsible for the cytosolic sulfation. Three distinct PST fractions were partially purified from the cytosol and were found to possess unique stereoselectivities toward HOP. Fraction 1 was most stereoselective, S/R-HOPS = 0.51, but was not inhibited by PCP, suggesting that it is a monoamine (M) form PST. Fraction 3 was the most active fraction and mimicked the cytosol in both stereoselectivity, S/R-HOPS = 0.73 vs. 0.72, and susceptibility to PCP inhibition, IC50 = 93 nM. The S/R-HOPS ratio produced by fraction 2 was 0.63. These data demonstrate the presence of multiple PST enzymes with differing stereoselectivities for the enantiomers of HOP in canine hepatic cytosol. Further studies with homogeneous PST isozymes, ideally from human tissue, and other chiral drugs are needed to define the enzymatic mechanism of this reaction and its role in chiral drug metabolism.

Animals↗
PubMed1989

Stereoselective uptake of atenolol into storage granules isolated from PC12 cells.

Atenolol has been shown to be stored and secreted from PC12 cells by calcium-dependent and stereoselective mechanisms. The present study was designed to determine if the cytoplasmic amine storage granule was the site for storage and release of atenolol and if the drug was, in fact, an enantiomeric selective substrate for the vesicular amine transport protein. Uptake of racemic [3H]atenolol and (-)-[3H]norepinephrine was studied in a vesicular preparation of storage granules isolated from PC12 cells. Uptake of both molecules was found to be ATP-dependent (80%) and to reach steady state in approximately 10 to 15 min. Uptake and storage was inhibited (95%) by either reserpine, an inhibitor of the vesicular amine carrier, or by nigericin which dissipates the proton gradient across the membrane. Uptake of neither compound was inhibited by desipramine, an inhibitor of uptake 1, or oligomycin, an inhibitor of mitochondrial adenosine triphosphatase. Furthermore, uptake of the (-)-enantiomer of atenolol was found to be approximately 5-fold greater than the (+)-enantiomer. Kinetic studies revealed a Km of 184 microM for (+/-)-atenolol and 79 microM for (-)-norepinephrine and Vmax values of 750 and 503 pmol/min/mg of protein for atenolol and norepinephrine, respectively. The interaction of the two compounds with the transport process was found to be kinetically competitive. In separate experiments, atenolol was also found to be transported stereoselectively into bovine adrenal chromaffin granule ghosts and to be ATP dependent (85%) and reserpine sensitive (44%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1989

A stereoselective central hypotensive action of atenolol.

Previous studies have demonstrated that propranolol can lower arterial pressure through an action within the central nervous system. The purpose of this study was to determine 1) whether the hydrophilic beta blocking drug atenolol which is devoid of membrane stabilizing activity can reduce arterial pressure through a central action and 2) whether this action is stereoselective for the (-)-, or beta receptor blocking enantiomer. Studies were conducted in the anesthetized spontaneously hypertensive (SH) rats in which the cardiovascular effects of (-)- and (+)- atenolol were compared after i.v. or intracisternal administration. Intravenous injection of 100 micrograms/kg of (-)-atenolol reduced mean arterial pressure 25 +/- 5 mm Hg (P less than .02) and lowered heart rate 58 +/- 7 bpm (P less than .02). The same dose of (+)-atenolol i.v. produced no significant changes in either mean arterial pressure or heart rate. Similarly, intracisternal (-)-atenolol, 66 micrograms/kg, significantly (P less than .05) reduced mean arterial pressure and heart rate whereas the same dose of the (+)-isomer was without effect. When the i.v. dose of (-)-atenolol was lowered to 33 micrograms/kg, heart rate was decreased markedly but mean arterial pressure was not reduced. In contrast, 33 micrograms/kg of intracisternal (-)- atenolol significantly reduced mean arterial pressure 17 +/- 6 mm Hg and reduced heart rate. These results suggest that atenolol possesses a central hypotensive action that is selective for the (-)-, beta receptor blocking enantiomer.

Animals↗
PubMed1988

Stereoselective delivery and actions of beta receptor antagonists.

These studies have revealed that the delivery and actions of beta receptor antagonist drugs are controlled by a cascade of stereoselective processes involving multiple enzymes, transport proteins and receptors. In essence, the free concentration of the pharmacologically active (-)-enantiomer species of these drugs presented to cell surface beta receptors appears to be a function of the stereoselective clearance by hepatic cytochrome P-450 isoenzymes, enantiomer selective binding to alpha 1-acid glycoprotein and albumin and perhaps predominantly by stereoselective sequestration (and release) by the vesicular amine transport protein within adrenergic neurons. Stereoselectivity in the clearance of beta blocking drugs, which can favor either the (+)- or (-)-enantiomer, only appears to be important for the lipophilic drugs which are cleared by hepatic metabolism. Such stereoselectivity is due to differential stereochemical substrate requirements of individual hepatic cytochrome P-450 isoenzymes. Interindividual variations in the stereoselectivity can occur as a result of differences in the amount and expression of cytochrome P-450 isoenzymes due to genetic predisposition or other factors. In the same context, we have observed a significant correlation between the extent and stereoselectivity of binding of beta blocking drugs to plasma proteins. This is another finding which suggests that variability in the expression of individual proteins involved in the beta blocking drug-protein cascade determines the free concentration of the pharmacologically active enantiomer. However, since most observations have been made in young normal subjects, the extent of stereoselectivity in metabolism, binding and other processes is unknown in the general population where steady-state plasma concentrations can vary widely due to multiple biological factors. The observations from neural studies support the concept that adrenergic nerve endings provide a depot for the stereoselective storage and release of the active enantiomer of beta receptor antagonists. The mechanism of this release appears to involve exocytotic secretion of drug that has been stereoselectively accumulated by the neurotransmitter storage vesicles. In terms of this idea, beta receptor antagonists released during nerve stimulation may achieve concentrations of the (-)-enantiomer within the adrenergic synapse greatly in excess of those found in plasma. Such a mechanism could significantly influence both the intensity and duration of beta receptor blockade in the heart, blood vessels, brain and other target tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Inhibitors of prostaglandin synthesis reverse the effects of chronic beta-receptor blockade to attenuate adrenergic neurovascular transmission in dogs.

The effects of acute and chronic treatment with beta-adrenergic receptor blocking drugs on peripheral adrenergic neurovascular transmission were investigated. Experiments were performed using the blood perfused gracilis muscle preparation in control dogs and in animals treated with single or repeated doses of beta-receptor antagonists. After 7 days of d,l-propranolol, l-propranolol, or atenolol administration, the arterial pressor response to sympathetic nerve stimulation was significantly reduced in treated dogs (p less than 0.05) when compared with control- or d-propranolol-treated animals. In comparison, acute beta blockade produced by a single intravenous dose of propranolol had no effect on the pressor response to nerve stimulation. Inhibition of fatty acid-cyclooxygenase activity by indomethacin or piroxicam enhanced the vasoconstrictor response to sympathetic nerve stimulation in chronic d,l-propranolol-, l-propranolol-, and atenolol-treated dogs, but had no effect on vascular neurotransmission in control-, chronic d-propranolol-, or acutely d,l-propranolol-treated animals. The vasoconstrictor response to intraarterial phenylephrine was not significantly altered by chronic propranolol treatment, and measurement of norepinephrine overflow during sympathetic nerve stimulation failed to reveal any difference in neurotransmitter release between control- and propranolol-treated dogs. The results indicate that chronic but not acute beta-adrenergic receptor blockade alters signaling at the neurovascular synapse to diminish adrenergic transmission. This effect does not appear to result from a change in postsynaptic alpha 1 receptors or from a decrease in norepinephrine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Enhanced exercise noradrenaline concentrations during propranolol treatment: a limiting factor in cardiac beta-adrenoceptor blockade.

Treatment with beta-adrenoceptor blocking drugs may result in augmented plasma concentrations of noradrenaline during exercise. The effect of propranolol on exercise heart rate and its relationship to plasma concentrations of propranolol and noradrenaline were examined in 10 hospitalized volunteers following treatment with propranolol, in doses of 80 mg and 320 mg daily. Responses to submaximal treadmill exercise during propranolol treatment and following discontinuation of the higher dose were compared to pre-drug and post drug placebo values. Exercise noradrenaline was increased by 67% over baseline values by treatment with the 320 mg daily dose of propranolol; this increment was present at 4 h and returned to baseline by 16 h after drug administration. Augmentation of exercise noradrenaline was correlated with plasma propranolol concentrations; the threshold concentration for this effect was 10-fold higher than the threshold for reduction in exercise heart rate. The effect of propranolol on heart rate was blunted in relation to the augmentation of exercise noradrenaline (P less than 0.001). These relationships suggest that, in patients taking high doses of propranolol, drug induced augmentation of plasma levels of noradrenaline during exercise may have physiologic importance. Enhanced effects on adrenergic receptors could have clinical relevance in certain groups of patients.

Adult↗
PubMed1988

Stereoselective secretion of atenolol from PC12 cells.

Stereoselective storage and release of the cardioselective beta adrenergic receptor antagonist atenolol was studied using cultured PC12 cells as a neural model. [3H]Atenolol efflux from preloaded PC12 cells was increased 4-fold in response to membrane depolarization by elevated extracellular potassium (50 mM). [3H]Norepinephrine release was enhanced 4.5-fold under the same conditions. Potassium-induced release of both [3H] atenolol and [3H]norepinephrine was inhibited completely in the absence of extracellular calcium. [3H]Atenolol release from PC12 cells was also reduced by the calcium channel antagonist nifedipine (IC50 = 1.6 +/- 0.5 nM). In addition, the calcium channel agonist BAY K8644 (1 microM) significantly enhanced potassium-induced [3H]atenolol efflux. After loading overnight, accumulation and storage of the (-)-enantiomer of atenolol by PC12 cells was found to be approximately 3-fold greater than that of the (+)-enantiomer. The (-)-enantiomer of atenolol was also preferentially released by 50 mM potassium with a (-)/(+)-enantiomer ratio of 3.6 to 1. The results support the existence within neurosecretory cells of storage and calcium-dependent release mechanisms which result in stereoselective secretion of the (-)-or active enantiomer of atenolol in response to membrane depolarization.

Animals↗
PubMed1987

Increased clearance of propranolol and theophylline by high-protein compared with high-carbohydrate diet.

The objective of this study was to determine whether changes in dietary protein and carbohydrate influence the oral clearance of propranolol, a high-clearance drug, and theophylline, a low-clearance drug. Six normal subjects studied in a clinical research center each received a single oral dose of propranolol, 80 mg, and theophylline, 5 mg/kg, after having been on each of two well-defined diets for a period of 10 days. When the diet was altered from high carbohydrate/low protein to low carbohydrate/high protein, the oral clearance of propranolol increased by 74% +/- 20% (mean +/- SE; range 9% to 156%; P less than 0.01) with no change in plasma half-life or plasma binding. This dietary change resulted in an increase in theophylline clearance of 32% +/- 6% (range 18% to 50%; P less than 0.02) and a corresponding decrease in plasma half-life of 26% +/- 6% (range 6% to 42%; P less than 0.05) with no alteration in the apparent volume of distribution. These observations reemphasize the importance of diet in drug disposition and suggest that the clearance of high-clearance drugs like propranolol is more susceptible than the clearance of low-clearance drugs to dietary manipulations, effects that may have to be considered in drug therapy.

Administration, Oral↗
PubMed1987

Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites.

The objective of this study was to examine the effect of cigarette smoking on the activities of the three primary pathways governing propranolol metabolism in human subjects, i.e., glucuronidation, side-chain oxidation and ring oxidation. A single 80-mg dose of propranolol p.o. together with 40 muCi of 4-[3H]propranolol was given to six smoking and seven nonsmoking, young, white, male subjects and the oral clearance of propranolol and the partial clearances through these pathways were determined. The oral clearance of propranolol was increased by 77% (P less than .02) in smokers compared with nonsmokers. This apparent induction of propranolol metabolism was due to a 122% increase in side-chain oxidation (P less than .001) and a 55% increase in glucuronidation (P less than .01). There was no significant effect of smoking on aromatic ring oxidation. Smokers had a 30% greater renal clearance of total metabolites (P less than .05), due mainly to a 53% greater renal clearance of the acidic propranolol metabolite naphthoxylactic acid (P less than .001). These data show a selective effect of smoking on propranolol metabolism and suggest that side-chain oxidation and glucuronidation are mediated by isoenzymes inducible by aromatic hydrocarbons. The selective effect of smoking on the renal clearance of the major propranolol metabolite naphthoxylactic acid may be due to induction of a renal transport protein.

Adult↗