Cytotoxic effects of the dietary flavones chrysin and apigenin in a normal trout liver cell line.

Many flavonoids have been shown to possess prooxidant properties, capable of causing oxidative stress, especially at larger doses. Here, we examined the potential cell toxicity caused by exposure to the hydroxylated flavones chrysin, apigenin, luteolin and quercetin in comparison to the methylated flavones 5,7-dimethoxyflavone and 3',4'-dimethoxyflavone in normal Rainbow trout hepatocytes. The hydroxylated flavones, especially chrysin, demonstrated cell toxicity and inhibition of DNA synthesis at very low (2 microM) concentrations. The cytotoxicity of chrysin may partially be due to its metabolism by myeloperoxidase, which was shown to be present in these normal trout liver cells (164pmol/(min mg protein)). In contrast, methylated flavones showed no significant metabolism by myeloperoxidase and no signs of toxicity, even at much higher concentrations. These results may be useful for further investigations of cytotoxicity of dietary flavonoids.

Phase I and pharmacologic study of a 3-hour infusion of paclitaxel followed by cisplatinum and 5-fluorouracil in patients with advanced solid tumors.

A Phase I and pharmacological study of paclitaxel administered as an outpatient, 3-h i.v. infusion just before a 5-day regimen of daily cisplatinum (CP) and a continuous infusion of 5-fluorouracil (5-FU) was performed in patients with advanced solid tumors. A secondary objective was to determine the objective response rate to this regimen. Forty-two patients were enrolled and were evaluable for toxicities. Eighteen patients were previously untreated, whereas the rest had received prior treatment with radiation (J. H. Schiller et al., J. Clin. Oncol., 12: 241-248, 1994), chemotherapy (M. J. Kennedy et al., Clin. Cancer Res., 4: 349-356, 1998), or both modalities (J. H. Schiller et al., J. Clin. Oncol., 12: 241-248, 1994). The paclitaxel dose was escalated from 100-135-170-200-225 to 250 mg/m2, whereas i.v. 5-FU and CP doses were fixed at 1.0 g/m2/day continuous infusion and 20 mg/m2/day, respectively, daily for 5 days. Granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/day) was administered s.c. from day 6, routinely after 250 mg/m2 dose of paclitaxel or after a lower dose of paclitaxel if ANC <500/microl or febrile neutropenia was observed. Patients were treated every 28 days. Plasma and urine samples were collected to determine the pharmacokinetics of paclitaxel. In previously untreated patients, the maximally tolerated dose of paclitaxel in the drug regimen was determined to be 170 mg/m2 without and 250 mg/m2 with G-CSF support. At the higher dose level, mucositis and thrombocytopenia were dose-limiting. In previously treated patients, these toxicities were observed at all dose levels of paclitaxel > or =135 mg/m2. With increasing doses of paclitaxel, a disproportionate increase in the peak concentrations, as well as the area under plasma concentration time-curve, was seen. This nonlinearity was due to saturable total body clearance and volume of distribution of paclitaxel (P < 0.001). The apparent plasma elimination half-life was unaffected by the dose of paclitaxel. CP and 5-FU had no apparent effect on the metabolism of paclitaxel. Among 32 patients evaluable for response, 22 demonstrated an objective response, including five complete remissions. Therefore, a regimen of 3-h infusion of 250 mg/m2 paclitaxel before CP and FU is tolerable with G-CSF (as above) support in previously untreated patients. The regimen also seems to be highly active against breast and esophageal cancers.

S-adenosyl-L-methionine: transcellular transport and uptake by Caco-2 cells and hepatocytes.

S-adenosyl-L-methionine (SAMe) is an endogenous molecule that is known to be protective against hepatotoxic injury. Although oral SAMe appears to be absorbed across the intestinal mucosa, its systemic bioavailability is low. The reason for this is unknown. Using the Caco-2 cell culture model for enterocyte absorption, we determined the mode by which SAMe is transported across this cell monolayer. We also determined the extent it is taken up by both Caco-2 cells and hepatocytes. In Caco-2 cells transport was observed in both apical to basolateral and basolateral to apical directions. The apparent permeability coefficients (Papp) appeared to be concentration independent and were similar in both directions (0.7x10(-6) and 0.6x10(-6) cm s-1, respectively), i.e. identical to that of the paracellular transport marker mannitol (0.9x10(-6) and 0.7x10(-6) cm s-1). This mode of transport was supported by a four-fold increase in the Papp for SAMe transport in Ca++-free buffer. Cellular uptake of SAMe was examined in both Caco-2 cells and cultured rat hepatocytes. Uptake by hepatocytes was not saturable in a concentration range of 0.001-100 microM. Accumulation by both cell types was very low, with a cell:medium ratio at equilibrium of only 0.2-0.5. This low cell accumulation supports the finding of paracellular transport as the only mode of cell membrane transport. Increased hepatocellular protection for SAMe may be accomplished by converting SAMe to a more lipid-soluble prodrug.

Time course of development of the antihypertensive effect of propranolol.

Ten patients with essential hypertension were hospitalized and treated with placebo, followed by their usual dose of propranolol. Systolic and diastolic blood pressure decreased significantly after the first dose of propranolol, and by the third day of propranolol treatment reached 84% to 92% of the maximum decrease achieved during the 6 days of treatment. Mean maximum falls in blood pressure were 13/12 mm Hg supine and 12/13 mm Hg standing. This development of the decrease in heart rate and blood pressure over 48 hours occurred in parallel with cumulation of propranolol to steady state in plasma. The decrease in diastolic, but not systolic, arterial pressure was directly related to pretreatment blood pressure, but not significantly related to pretreatment plasma renin activity (PRA) or change in PRA. Thus, single doses of propranolol lowered blood pressure in patients with essential hypertension, and with continued therapy, near maximum antihypertensive effects were achieved within 48 hours.

Massive propranolol metabolite retention during maintenance hemodialysis.

Eight outpatients on long-term hemodialysis receiving propranolol therapy were studied on a nondialysis day, 11 +/- 1 hr after the last dose. Steady-state daily dosage of propranolol averaged 225 +/- 36 mg (range, 80 to 400). Plasma concentrations of propranolol and three of its metabolites were measured by gas chromatography--mass spectrometry (x +/- SEM): propranolol, 47 +/0 17 ng/ml; propranolol glucuronide, 2.119 +/0 597 ng/ml; 4-hydroxypropranolol glucuronide, 789 +/- 149 ng/ml; and naphthoxylactic acid, 4,357 +/- 727 ng/ml. The plasma levels of these metabolites were 18, 20, and 29 times, respectively, as high as in patients with normal renal function and correlated well with the dose of propranolol. The total concentration of these metabolites exceeded the concentration of propranolol to 239 times (range 74 to 476). Four long-term hemodialysis patients on propranolol were hospitalized to ensure compliance. Plasma levels of propranolol and of the three metatolites were followed during a dosage interval. Plasma propranolol correlated well with dose (r = 0.94) and declined with approximately normal half-lifes of 3.2 to 5.4 hr. There was little variation in the extremely high plasma levels of the three metabolites during a dosage interval. The total metabolite to propranolol plasma concentration ratio in these four patients ranged from 109 to 705. The correlation between total metabolite concentrations and propranolol dose was striking (r = 0.997). Massive retention of propranolol metabolites occurs uniformly in uremia, is highly predictable from the dose, and could have important clinical implications.

Kinetic and clinical observations in cyanotic children on propranolol therapy.

The kinetics of propranolol and its metabolite 4-hydroxypropranolol were determined together with heart rate and blood pressure responses in five cyanotic children on long-term propranolol therapy and after abrupt withdrawal. The daily dose range of propranolol was 2.4 to 4.4 mg/kg. Mean steady-state plasma propranolol concentrations, 16.5 to 114 ng/ml, were linearly related to dose (r = 0.93; p < 0.02) above a threshold dose of 1.8 mg/kg/day. There was excellent correlation (r = 0.96; p = 0.01) between concentrations and reduction in heart rate (delta HR, 14 to 27.5 beats/min), which also suggested a maximum heart rate response at plasma propranolol concentrations of 80 to 100 ng/ml. There was an inverse relationship between the plasma concentrations of 4-hydroxypropranolol and dose. On abrupt withdrawal of long-term propranolol therapy, plasma levels declined with a propranolol half-life (t1/2) of 3.9 to 6.4 hr, which correlated with the hemoglobin value. The 4-hydroxypropranolol t1/2 was 5.2 to 7.5 hr. Heart rates returned to normal after approximately 36 hr. Changes in blood pressure were minimal.

Stereoselective binding of propranolol to human plasma, alpha 1-acid glycoprotein, and albumin.

Our aim was to determine possible stereoselectivity in the plasma binding of propranolol. Equilibrium dialysis with plasma from seven healthy subjects and a deuterium-labeled pseudoracemate of propranolol was used. Plasma binding of the propranolol enantiomers differed with the unbound fraction of (-)-propranolol (22 +/- 2%; mean +/- SE) being smaller than that of (+)-propranolol (25.3 +/- 1.9%). The (-)/(+)-propranolol ratio for the unbound fraction, a measure of the stereoselectivity, was 0.86 +/- 0.02. There was an inverse correlation between the unbound (-)/(+)-propranolol ratio in individual subjects and overall binding of (+/-)-propranolol, indicating greater stereoselectivity at higher total binding. To assess the site of the stereoselective binding to plasma proteins, the binding of (+)- and (-)-propranolol to human alpha 1-acid glycoprotein (AGP) and human serum albumin (HSA) was examined. The binding to AGP was stereoselective for (-)-propranolol with a (-)/(+)-propranolol ratio for the unbound fraction of 0.79 +/- 0.01, whereas (+)-propranolol was bound to a greater extent to HSA with a (-)/(+)-propranolol ratio for the unbound fraction of 1.07 +/- 0.01. Although these results demonstrate opposite stereoselectivity in the binding of (+)- and (-)-propranolol to AGP and HSA, the stereoselective binding of (-)-propranolol to AGP predominates in plasma. This stereoselective plasma binding of the (-)-enantiomer of propranolol could limit the access of this more active enantiomer to beta-receptors or other active sites. The uptake of propranolol by red blood cells was not stereoselective.

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.

Propranolol metabolism in normal subjects: association with sex steroid hormones.

The objective of this study was to determine the potential role of circulating testosterone and estradiol in regulation of the activity of the sex-dependent pathways of propranolol metabolism (i.e., alpha-naphthoxylactic acid and propranolol glucuronide). The pharmacokinetics of a single 80 mg oral dose of propranolol and the plasma levels of the sex steroid hormones were therefore determined in normal volunteers. In 33 young men there was a positive correlation between the testosterone levels and the propranolol clearances through both alpha-naphthoxylactic acid (p < 0.001) and propranolol glucuronide (p < 0.002), as well as the total clearance (p < 0.05), but not through aromatic ring hydroxylation. Testosterone cypionate administration led to an increased clearance of propranolol through alpha-naphthoxylactic acid in nine of the 11 men studied, further supporting a stimulatory effect of testosterone on propranolol metabolism. In 23 young women there was no significant association between the circulating levels of either estradiol or testosterone and any of the clearances of propranolol. These observations may be clinically relevant for propranolol therapy and may provide improved insight into the influence of gender and circulating gonadal hormones on drug metabolism in humans.

Propranolol glucuronide cumulation during long-term propranolol therapy: a proposed storage mechanism for propranolol.

The comparative disposition of propranolol glucuronide (PG) and propranolol was determined in 35 patients with hypertension or coronary artery disease during initiation of propranolol therapy, during steady-state conditions, and after discontinuation of propranolol (dose range, 40 to 960 mg daily, every 6 hr). The 2.3-fold PG cumulation in plasma was identical to propranolol cumulation. PG plasma levels were about 4 times as high as propranolol levels over the whole dose range. Unexpectedly slow terminal elimination rate of propranolol (t1/2 approximately 16 to 24 hr) on discontinuation of propranolol appeared to be related to equally slow PG elimination. PG and propranolol could be detected in plasma and urine up to 3 to 5 days after propranolol discontinuation. The PG formed in man was deconjugated to propranolol in the dog after intravenous administration, suggesting that PG may serve as a storage pool for propranolol. Observations consistent with systemic and enteric deconjugation of PG, including enterohepatic recirculation, may, at least in part, explain the observed propranolol cumulation as well as the slow elimination of propranolol after its discontinuation. PG renal clearance (29 to 70 ml/min) and PG plasma levels were highly dependent on glomerular filtration rate, suggesting that PG may cumulate abnormally in patients with severe renal disease.

4-Hydroxypropranolol and its glucuronide after single and long-term doses of propranolol.

The disposition of the pharmacologically active 4-hydroxypropranolol (HO-P), its glucuronic acid conjugate (HO-P-G), and propranolol were compared after single intravenous and oral doses of propranolol in 6 normal subjects and after long-term therapy in 32 patients with hypertension or coronary artery disease. The areas under the plasma concentration/time curves (AUCoo, ng . hr/ml) after 4-mg intravenous doses of propranolol were 6.6 +/- 2.2 (mean +/- SEM) for HO-P and 55 +/- 11 for propranolol. After 20- and 80-mg oral doses the AUCoo for HO-P were 59 +/- 9 and 162 +/- 21 and for propranolol were 72 +/- 9 and 306 +/- 46. Peak HO-P concentrations were reached at 1 to 1.5 hr after the oral doses. Although there was a rapid decline in plasma HO-P between 1.5 and 3 hr when HO-P-G was still rising to levels above HO-P levels 3.5- to 5-fold, the apparent half-lifes (t1/2s) after 3 hr were in the same range for HO-P, HO-P-G, and propranolol (3.0 to 4.2 hr). While during long-term therapy plasma HO-P rose over the whole dose range (40 to 960 mg daily) in an apparently linear fashion, the HO-P/propranol plasma level ratio fell from 1.07 +/- 0.13 at 40 mg daily to only 0.09 +/- 0.01 at 640 mg daily. Plasma HO-P-G rose exponentially with dose and demonstrated significant cumulation. HO-P and HO-P-G in urine accounted for about 9% of long-term propranolol doses. This study suggests a significant contribution of HO-P to pharmacologic effects, in particular at low single and long-term oral doses of propranolol and saturation of naphthalene ring oxidation as a main determinant of propranolol bioavailability.

Biologic determinants of propranolol disposition: results from 1308 patients in the Beta-Blocker Heart Attack Trial.

Our objective was to identify biologic determinants of propranolol serum levels in 1308 patients after myocardial infarction (MI). Patients had had their MI within the previous month. A steady-state propranolol dosage of 40 mg every 8 hours produced a mean trough concentration of 42 ng/ml with extremely great (fiftyfold) interindividual variability. Univariate and multivariate analyses suggested that this variability was the result of many biologic factors. Serum levels were higher in women, in older patients, and in patients receiving concomitant therapy with other antiarrhythmic drugs. Serum levels were also higher in patients with elevated serum creatinine and lactate dehydrogenase levels. Serum levels were lower in black patients than in white patients. Also, serum levels in smokers were lower than those in nonsmokers, but only markedly so in the outpatient setting (6 months after the MI). The influence of sex and race on drug disposition has not previously been reported for beta-blocking drugs. Although a genetic deficiency in the oxidative metabolism of propranolol has been indicated, the frequency distribution of serum propranolol levels did not demonstrate a bimodal distribution for genetically distinct populations.

Presystemic and systemic glucuronidation of propranolol.

The relative importance of presystemic and systemic glucuronidation of propranolol was examined in normal subjects given single oral and intravenous doses of propranolol. The areas under the plasma concentration--time curves (AUCs) of propranolol glucuronide (PG), 41 +/- 15 ng . hr/ml, and propranolol, 48 +/- 15 ng . hr/ml, were of the same order after the intravenous dose (0.05 mg/kg). After oral doses of 20 and 80 mg, the AUCs of PG were 302 +/- 105 and 1,398 +/- 409 ng . hr/ml; these were 7 times the AUCs of propranolol, 44 +/- 15 and 220 +/- 38 ng . hr/ml. The time lapse to peak concentration, 1.5 to 3.0 hr, and the plasma half-life, 3.2 to 3.7 hr, were the same for PG and propranolol. These results demonstrate glucuronidation as an important determinant of propranolol bioavailability.

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)

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Food-induced increase in propranolol bioavailability--relationship to protein and effects on metabolites.

The influence of a meal on the disposition and metabolism of oral propranolol was examined in six normal subjects. The meal induced a mean 53% increase in propranolol bioavailability (range 2% to 92%; P less than 0.01) without affecting time to maximum concentration, half-life, or the amount of unchanges drug in urine. There was no effect on the plasma concentrations of 4-hydroxypropranolol or four other metabolites. The increased bioavailability was linearly related to the protein content of the meal (r = 0.884, P less than 0.02) above a threshold content of about 7 gm.

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis.

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.

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.

Ring-hydroxylated propranolol: synthesis and beta-receptor antagonist and vasodilating activities of the seven isomers.

Propranolol (Inderal; 1) is extensively metabolized in man. Metabolites of interest pharmacologically include ring-hydroxylated propranolols (1a-g). In order to identify these ring-oxidized products and to study the effect of hydroxyl position on biological activity, we have synthesized all seven isomers. With the exception of 1b and 1g, the desired compounds were prepared by alkylation of the respective methoxy-1-naphthols with epichlorohydrin and reaction of the resulting epoxide with isopropylamine. Cleavage og the methyl group in fused pyridine hydrochloride afforded 1a,c-f. 1g was prepared by the direct alkylation of 1,8-naphthalenediol (17) with epichlorohydrin, followed by reaction with isopropylamine. 1b was synthesized by treating 2-naphthol (9) with chlorine gas and then treating the resulting 1,1-dichloronaphthalen-2(1H)-one (10) with sodium allyl oxide. Acetylation of the hydroxy function and epoxidatrion of the allyl group, followed by relation with isopropylamine, gave 3'-hydroxy-4'-chloropropranolol (15). Dechlorination gave 1b. All of the racemic hydroxylated propranolols produced beta blockade and direct vasodilation in anesthetized dogs. The potency is strongly dependent upon the position of the hydroxyl group, i.e., 1e is 4 times as potent as 1 as a beta receptor antagonist, whereas 1a, 1b, and 1g are all significantly less potent than 1. For direct vasodilation, 1a and 1g are equipotent to 1, while 1b-f are much less potent. The potencies of the compounds were also compared with their 1-octanol/pH 7.4 buffer distribution coefficients; the direct vasodilating potency was found to increase with increasing lipophilicity, while the beta-adrenergic antagonist potency decreased.

Synthesis of 4'-hydroxypropranolol sulfate, a major non-beta-blocking propranolol metabolite in man.

4'-Hydroxypropranolol sulfate was recently identified as a major metabolite of propranolol (Inderal). In order to confirm the structure and to further study disposition and biological activity, we have synthesized 8 with use of 1,4-naphthoquinone as the starting material. Reduction and alkylation with benzyl iodide gave 4-(benzyloxy)naphthol. Sulfation and chlorosulfuric acid in N,N-dimethylaniline gave potassium 1-(benzyloxy)-4-naphthol sulfate. Catalytic hydrogenation, alkylation with [[[(trifluoromethyl)sulfonyl]oxy]methyl]oxirane, and amination in isopropylamine gave 8. Racemic 8 was found to be 100-1000 times less potent than racemic propranolol as a beta-adrenergic receptor blocking agent in the dog.