Metabolism Of Propranolol Research Articles

非ステロイド系抗炎症剤（４８０１５６‐Ｓ）のプロプラノロール，ジアゼパム，ワーファリン，トルブタミド代謝に及ぼす影響

非ステロイド系抗炎症剤（４８０１５６‐Ｓ）のプロプラノロール，ジアゼパム，ワーファリン，トルブタミド代謝に及ぼす影響

A computer simulation of the food effect: Transient changes in hepatic blood flow and michaelis‐menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol

A physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis-Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal. The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg-1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax.

ラットにおけるプロプラノロールならびにリドカイン代謝の系統差

ラットにおけるプロプラノロールならびにリドカイン代謝の系統差

Halothane inhibition of propranolol metabolism is stereoselective.

Propranolol, like many drugs, is used clinically as a racemic mixture. The major pharmacodynamic effects of propranolol, however, are mediated by the (-)-isomer, which is 100 times as potent as the (+)-isomer. The two isomers also differ in their pharmacokinetic characteristics. To determine whether halothane anesthesia stereo-selectively inhibits the metabolism of racemic propranolol, eight male mongrel dogs were studied. On the first day of the study, 40 mg racemic propranolol was infused into the portal vein and arterial blood samples were obtained over the following 4 h for the measurements of (+)- and (-)-propranolol concentrations by HPLC. The study was repeated 24 h later during 2 MAC halothane anesthesia, when the intrinsic clearance of total propranolol was decreased by 67.5 +/- 5%, from 6.14 +/- 1.1 1/min to 1.84 +/- 0.4 1/min (P less than 0.05). The decrease in intrinsic clearance was stereoselective, (-)-propranolol being affected to a greater extent than (+)-propranolol; thus, the decrease in the clearance of (-)-propranolol, from 10.96 +/- 2.71/min to 2.6 +/- 0.71/min (73 +/- 5%) was significantly (P less than 0.05) greater than the decrease in the clearance of (+)-propranolol, (62 +/- 3%) from 4.3 +/- 0.8 1/min to 1.5 +/- 0.3 1/min. Furthermore, the ratio of the intrinsic clearance of (-)-propranolol to the intrinsic clearance of (+)-propranolol was significantly (P less than 0.05) reduced by halothane anesthesia, from 2.42 +/- 0.29 to 1.69 +/- 0.11. Stereoselective inhibition of propranolol metabolism results in proportionally higher concentrations of (-)-propranolol during halothane anesthesia than are present in awake dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple pathways of propranolol's metabolism are inhibited by debrisoquin.

We investigated the effect of debrisoquin on propranolol metabolism in six normal subjects who were extensive metabolizers of debrisoquin. Each subject was studied on two occasions. On the first occasion, each subject received oral propranolol (80 mg) alone; on the second occasion, 7 days later, each subject received a dose of propranolol (80 mg) 30 minutes after the administration of oral debrisoquin (40 mg). Oral propranolol clearance was reduced 33% +/- 16% (p less than 0.05) by the administration of debrisoquin. As predicted, the 4-hydroxypropranolol partial metabolic clearance was significantly (p less than 0.05) inhibited by debrisoquin. However, the side-chain oxidation pathway, as measured by naphthoxylactic acid, was also significantly (p less than 0.05) inhibited by debrisoquin. Debrisoquin administration did not change the renal clearance of any of the metabolites. These data support the usefulness of the in vivo inhibition model in the prediction of cosegregation of routes of metabolism. However, for propranolol, pathways of its metabolism that are not thought to cosegregate with debrisoquin was also inhibited.

Effects of metabolic inhibitors and incubation temperature on the saturable uptake of propranolol by isolated rat lung tissue

The effects of several metabolic inhibitors (50 microM) on the initial uptake rate of propranolol (0.5 to 500 micrograms mL-1) by the minced lungs (0.4 g) isolated from 7-week-old rats has been investigated in oxygenated, pH 7.4 Krebs-Ringer bicarbonate buffer solution (20 mL) containing 3% BSA at 37 degrees C for 5 min. The effect of the incubation temperature was also examined. Metabolism of propranolol was almost insignificant (i.e. less than 1.3% of the initial load). The overall initial uptake rate was considered to be a combination of apparent linear transport and saturable processes. For the control uptake rate, the linear transport rate constant was 1.26 +/- 0.16 g-1 mL-1 min-1, while Vmax and Km' of the capacity limited uptake process were estimated as 0.727 +/- 0.074 mg g-1 min-1 and 24.8 +/- 2.71 micrograms mL-1, respectively. No metabolic inhibitor tested had an effect on the linear transport rate of propranolol but 2,4-dinitrophenol and potassium cyanide inhibited saturable uptake rate (i.e. Vmax) of propranolol significantly (P less than 0.01) while ouabain, phloridine and iodoacetic acid did not do so significantly. Reduction of the incubation temperature to 15 degrees C decreased and at 25 degrees C tended to decrease, both linear transport and saturable uptake rates.

The effect of a single treatment with cigarette smoke on the blood levels and hemodynamic effects of propranolol in rats.

The effect of a single treatment with cigarette smoke on the blood levels and hemodynamic effects of propranolol in rats was studied. Pentobarbital sleep time was not affected whereas zoxazolamine paralysis time was shortened 72% in rats, 24 h after the cigarette smoke exposure. The beta-adrenoceptor blocking effect of propranolol observed at 10 and 20 min time intervals was abolished in rats exposed to cigarette smoke 24 h after the exposure. The blood propranolol concentrations were decreased in rats pretreated with phenobarbital, 3,4-benzpyrene and ethanol as well as in cigarette smoke exposed rats. Among several factors that could influence propranolol metabolism, in this study, enzyme induction is suggested to be dominant.

Specific Age-dependence in Capacity-limited Uptake of Propranolol by Isolated Rat Lung

To investigate the effect of age on the pulmonary uptake of propranolol, minced tissue (0.4 g) of lungs isolated from 3- to 104-week-old rats was incubated with the drug (1 to 500 micrograms mL-1) prepared in oxygenated, pH 7.4 Krebs-Ringer bicarbonate buffer solution (20 mL) containing 3% BSA for 60 min at 37 degrees C. In any age-group the metabolism of propranolol was not significant (i.e. less than 0.6% of any initial load) under the present in-vitro conditions. The extent of uptake after the incubation with 2.5 micrograms mL-1 of the drug was largest in the 7 weeks (i.e. 82% of the initial load) and relatively small in the 3(64%), 24(61%), 52(51%) and 104(48%) week old rats. Similar, specific age-dependence was observed in the tissue-to-medium concentration ratio of the drug. In any age-group, the initial uptake rate obtained in the first 5 min of the incubation was found to be a combination of apparently linear transport and saturable (capacity-limited) processes. There was a marked, specific age-dependence in the capacity-limited uptake rate. Although Km' value was almost equivalent in any age-group (i.e. 24.4 to 25.4 micrograms mL-1), Vmax exhibited a specific age-dependence by yielding the highest value in 7 weeks (0.726 +/- 0.101 mg g-1 min-1) and relatively low values in 3 (0.501 +/- 0.082 mg g-1 min-1), 52 (0.410 +/- 0.088 mg-1 g-1 min-1) and 104 (0.397 +/- 0.074 mg g-1 min-1) weeks.

Effects of bovine serum albumin and recirculation rate on the uptake of propranolol by rat perfused lung

Lungs isolated from 7-week-old rats were perfused with pH 7.4, oxygenated Krebs-Ringer bicarbonate buffer solution containing 2.5 micrograms mL-1 of propranolol and 3 to 5% BSA at the recirculation rate of 4 to 16 mL min-1, at 37 degrees C for 60 min. The extent of propranolol metabolism after 60 min was less than 2.3% of the initial load under any in-vitro perfusion condition. Therefore, the amount disappearing from the perfusion medium was considered as being predominantly that taken up by tissue. Under all experimental conditions, perfusate drug level declined bi-exponentially with time. Apparent in-vitro pulmonary clearance of propranolol was not affected by the increase of BSA level from 3 to 5%. When the perfusate BSA level was fixed at 3%, the lowest recirculation rate (4 mL min-1) yielded the smallest clearance (about 0.15 mL min-1 g-1) but almost constant clearance value (about 0.40 mL min-1 g-1) was obtained at the rate ranging from 8 to 16 mL min-1. The tissue to medium concentration ratio of propranolol, after the perfusion with 3 to 5% BSA at the rate of 8 to 16 mL min-1, was approximately 35, whereas that with 3% BSA at 4 mL min-1 was reduced to about 20. The findings suggest evidence for flow-dependent in-vitro pulmonary clearance of propranolol.

Influence of debrisoquin phenotype on the inducibility of propranolol metabolism.

The effects of rifampin (600 mg) once daily for 22 days on the total and fractional metabolic clearances of propranolol were determined in a group of six genetically extensive (EM) and six poor metabolizers (PM) of debrisoquin. The impaired ability of PMs to metabolize propranolol to the ring-oxidized metabolite 4-hydroxypropranolol was confirmed. The total oral clearance of propranolol increased about fourfold in both phenotypes from 219.2 +/- 52.8 to 976.7 L/hr in the EMs and from 75.0 +/- 12.6 to 289.8 +/- 78.2 L/hr in the PMs. The extent of induction of glucuronidation was similar in the two groups. 4-Hydroxylation was induced in both phenotypes but the increase was fifteenfold greater in EMs than in PMs. This would imply that the cytochrome P-450 determined by the debrisoquin allele or some coinherited 4-hydroxylase(s) was induced to a greater extent in EMs than PMs.

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)

Reduction of first-pass metabolism of propranolol after oral administration of ester prodrugs

For orally administered drugs, first=pass metabolism by the liver is a formidable barrier to efficient delivery. Extensive first-pass metabolism, in addition to decreasing the percentage of dose reaching its intended site of action, often leads to significant variability in bioavailability, necessitating careful monitoring of patient blood levels. While first-pass metabolism can be avoided by selecting alternate routes of administration (i.v., transdermal, rectal, etc.), the oral route is generally preferred. Rational approaches for minimizing first-pass metabolism would therefore be quite valuable. Propranolol, used extensively in the treatment of angina pectoris, hypertension, and cardiac arrhythmia, has been shown to undergo extensive presystemic metabolism after oral administration leading to reduced bioavailabihty (Paterson et al., 1970; Shand et al., 1970; Lo et al., 1982) and significant inter-subject variability in blood levels (Kornhauser et al., 1978). Garceau et al. (1978) have shown that the hemisuccinate ester of propranolol, when administered orally to beagle dogs, yields propranolol levels 8 times higher than after an equivalent dose of propranolol hydrochloride.

Regioisomeric products of propranolol metabolism. The monomethyl ethers of 3,4-dihydroxypropranolol and of 3,4-dihydroxypropranolol glycol.

Regioisomeric products of propranolol metabolism. The monomethyl ethers of 3,4-dihydroxypropranolol and of 3,4-dihydroxypropranolol glycol.

Effect of inflammation on the metabolism of antipyrine, lidocaine and propranolol in isolated rat hepatocytes.

A decrease of the hepatic intrinsic clearance could contribute to the increase of the plasma concentrations of alpha 1-acid glycoprotein-bound drugs such as propranolol in animals and humans with inflammation. Therefore, the influence of inflammation upon the metabolism of propranolol and another high clearance drug, lidocaine, and of the low clearance drug antipyrine, was studied in isolated rat hepatocytes. For comparative purposes, the influence of the enzyme inhibitor SKF 525A (100 mg/kg i.p.) was also evaluated. Turpentine pretreatment of the rats significantly decreased the metabolism of the three drugs by the hepatocytes; the decrease was least pronounced for propranolol. The inhibitory effect of turpentine-induced inflammation was somewhat lower than that of SKF 525A. These results are in agreement with the results found for the same drugs in the 9,000-g supernatant fraction of the rat liver and point to a marked decrease of intrinsic clearance in some types of inflammation.

The metabolism of propranolol (ICI 45,520, Inderal) and xamoterol (ICI 118,587, Corwin) by isolated rat hepatocytes: in vivo-in vitro correlations.

1. The metabolism of two compounds which undergo predominantly Phase I (propranolol) and Phase II (xamoterol) metabolism in vivo has been studied in isolated rat hepatocytes. 2. Propranolol was rapidly metabolized by rat hepatocytes to a number of metabolites which correlated well with those observed in vivo. The effect of saturable metabolism on the in vitro clearance of propranolol at high substrate concentrations was very similar to the changes observed in vivo. 3. Xamoterol was metabolized by rat hepatocytes to produce mainly xamoterol glucuronide, with the sulphate conjugate of xamoterol representing a minor component. The low rate of formation of xamoterol sulphate is probably due to the low affinity of xamoterol for the sulphotransferase enzyme, since supplementation with inorganic sulphate did not significantly alter the rate of sulphation; the sulphotransferase system of these hepatocytes was however shown to be active in the metabolism of phenol. 4. The correlations observed between the known routes of metabolism of propranolol and xamoterol in vivo and those observed in isolated hepatocytes support the utility of isolated hepatocytes as a predictive model of metabolic events in vivo.

Clinical pharmacokinetics and endocrine disorders. Therapeutic implications.

Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin, anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of disease-induced changes in hepatic drug metabolism, protein binding and renal function. In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in alpha 1-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin, antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted beta-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualization and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with beta-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggest care with dosage and frequent monitoring of response are warranted. Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steady-state propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required.(ABSTRACT TRUNCATED AT 400 WORDS)

Irreversible binding and metabolism of propranolol by human liver microsomes—Relationship to polymorphic oxidation

Studies were performed to investigate the irreversible binding and oxidative metabolism of propranolol in human liver microsomes and the relationship of binding and metabolism to the polymorphic oxidation of debrisoquine. Incubation of microsomes with 14C-labelled propranolol in the presence of a NADPH-generating system gave rise to irreversible binding which increased linearly with time and became saturated at high substrate concentrations. The extent of binding was decreased by the exclusion of cofactors, boiling, anaerobic conditions, and the addition of reduced glutathione and SKF-525A. Trichloropropene oxide had a negligible effect on cofactor-dependent binding. However, debrisoquine, antipyrine and phenacetin decreased binding to a considerable extent. The latter compound abolished cofactor-dependent binding completely at the concentration used (1 mM). Electrophoresis of microsomes which had been incubated with tritiated propranolol revealed that binding was probably occurring to a large number of proteins particularly in the 40,000–90,000 molecular weight range. Glutathione, debrisoquine and antipyrine did not inhibit the 4'-hydroxylation and N-deisopropylation of propranolol. In contrast, phenacetin exerted a very potent inhibitory action on both routes of metabolism. It is concluded that (a) a product or products of propranolol oxidation bind irreversibly but non-selectively to human liver microsomal protein, (b) the enzyme system responsible for the activation of propranolol appears to be related more closely to the cytochrome P-450 system which metabolises phenacetin than to that metabolising debrisoquine, and (c) radiolabelled propranolol is not a sufficiently specific probe for studying these cytochrome P-450 systems.

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

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

ChemInform Abstract: Chemical and Stereochemical Aspects of Propranolol Metabolism. Diastereomeric 1‐(1‐Hydroxy‐2‐propylamino)‐3‐(1‐naphthoxy)‐2‐propanols Produced by Rat Liver Microsomal ω‐Hydroxylation.

ChemInformVolume 18, Issue 11 Isocyclic Compounds ChemInform Abstract: Chemical and Stereochemical Aspects of Propranolol Metabolism. Diastereomeric 1-(1-Hydroxy-2-propylamino)-3-(1-naphthoxy)-2-propanols Produced by Rat Liver Microsomal ω-Hydroxylation. H. U. SHETTY, H. U. SHETTY Dep. Med. Chem., Sch. Pharm., Univ. Wash., Seattle, WA 98195, USASearch for more papers by this authorW. L. NELSON, W. L. NELSON Dep. Med. Chem., Sch. Pharm., Univ. Wash., Seattle, WA 98195, USASearch for more papers by this author H. U. SHETTY, H. U. SHETTY Dep. Med. Chem., Sch. Pharm., Univ. Wash., Seattle, WA 98195, USASearch for more papers by this authorW. L. NELSON, W. L. NELSON Dep. Med. Chem., Sch. Pharm., Univ. Wash., Seattle, WA 98195, USASearch for more papers by this author First published: March 17, 1987 https://doi.org/10.1002/chin.198711144AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume18, Issue11March 17, 1987 RelatedInformation

Chemical and stereochemical aspects of propranolol metabolism. Diastereomeric 1-(1-hydroxy-2-propylamino)-3-(1-naphthoxy)-2-propanols produced by rat liver microsomal omega-hydroxylation.

A new metabolic pathway of terminal hydroxylation (omega-hydroxylation) of the N-isopropyl group of propranolol (1) was established. Selected ion-monitoring GC-MS analysis, based on use of the synthesized mixture of diastereoisomers of 1-(1-hydroxy-2-propylamino)-3-(1-naphthoxy)-2-propanol (2) as a standard, established formation of both diastereoisomers of 2 as metabolites of 1. These diastereoisomers were formed in unequal amounts when 1, its hexadeuterated analogue 8 or heptadeuterated analogue 9, were incubated in the presence of the rat liver microsomal fraction. Authentic (2R,2"S)-2, obtained from the amide formed from (2S)-3-(1-naphthoxy)-2-hydroxypropionic acid [(2S)-5] and (2S)-alaninol by diborane reduction, facilitated examination of stereochemical aspects of this process. From incubations of the enantiomers of 1 and pseudoracemic propranolol [equimolar (2R)-propranolol-3,3-d2 and (2S)-propranolol-d0] in the presence of the rat liver microsomal fraction, we established that the diastereomeric products were formed in the order (2S,2"S)-2 approximately equal to (2S,2"R)-2 greater than (2R,2"R)-2 greater than (2R,2"S)-2. (2S)-1, which was metabolized to 2 to a greater extent than (2R)-1, showed no stereoselectivity, affording about equal amounts of (2S,2"S)-2 and (2S,2"R)-2. (2R)-1, which was metabolized to 2 to a lesser extent, afforded considerably more (2R,2"R)-2 than (2R,2"S)-2. omega-Hydroxylation was a minor metabolic pathway in the microsomal incubation. About 2000X less 2 than 1-amino-3-(1-naphthoxy)-2-propanol (3), the product of N-dealkylation of 1, was formed.