Richard P. Koshakji

Racial Differences in Drug Response

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.

Polymorphic ability to metabolize propranolol alters 4‐hydroxypropranolol levels but not beta blockade

The ability to hydroxylate debrisoquine is known to be polymorphically distributed, with about 8% to 9% of the North American Caucasian population being poor metabolizers. We have shown that the ability to 4‐hydroxylate propranolol is also polymorphically determined and that it cosegregates with ability to metabolize debrisoquine, such that poor debrisoquine metabolizers produce much less 4‐hydroxypropranolol (4‐OH propranolol) than do extensive metabolizers. There was no significant difference, however, between plasma propranolol concentrations after either single or multiple doses in the two groups. Despite the substantial difference in production of the pharmacologically active 4‐OH metabolite, no difference was seen in the extent of β‐blockade induced in the extensive and poor metabolizers, which implies that 4‐OH propranolol does not contribute substantially to β‐blockade.

Ultra‐short‐acting beta‐blockade: A comparison with conventional beta‐blockade

Esmolol is a β1‐selective adrenoceptor blocker that is rapidly metabolized by blood and liver esterases. The β‐receptor and hemodynamic effects of esmolol were determined in a group of 12 healthy men and were compared with those induced by both oral and intravenous propranolol. Esmolol was rapidly effective in inducing at least 90% of steady‐state β‐blockade within 5 minutes of either initiating or changing the esmolol infusion rate. More importantly, when esmolol infusion was discontinued the β‐blockade had totally disappeared by 18 minutes after esmolol, 300 µg/kg/min, and had been reduced by 50% after 750 µg/kg/min. In contrast, 30 minutes after discontinuation of a propranolol infusion, there was no change in the level of β‐blockade. Propranolol was much more potent at blocking isoproterenol‐induced tachycardia (dose ratio 33.5 ± 2.5) than was even the highest dose (750 µg/kg/min) of esmolol (dose ratio 13.1 ± 1.0). The same dose of intravenous propranolol was approximately equipotent to oral propranolol, 40 mg every 8 hours (dose ratio 33.5 ± 2.5 and 34.5 ± 3.6, respectively). In contrast, propranolol, 40 mg every 8 hours, and esmolol, 300 µg/kg/min, were equipotent in antagonizing exercise‐induced tachycardia (40.1% ± 2.3% and 42.7% ± 3.2%, respectively). Esmolol had striking hypotensive effects. Systolic blood pressure fell by 20 mm Hg during esmolol infusions of 750 µg/kg/min. Esmolol appears to be a potent β1‐selective adrenoceptor antagonist with a particularly strong hypotensive effect. It is likely to be very useful in the treatment of hemodynamically unstable patients and may be useful in the emergency treatment of hypertension.

The Effect of Halothane on Drug Disposition: Contribution of Changes in Intrinsic Drug Metabolizing Capacity and Hepatic Blood Flow

Several studies have shown that halothane may influence drug disposition in animals and humans, but the mechanism remains unclear. The relative contributions of changes in metabolizing capacity and hepatic blood flow to altered drug disposition were investigated during halothane anesthesia, using propranolol as a model compound. The studies were performed on six dogs on three separate days; first, the day before anesthesia, second, during halothane (2.0 MAC) anesthesia, and third, 24 h after anesthesia. Each dog simultaneously received 40 mg unlabeled propranolol directly into the portal vein and 200 mCi of 3H-propranolol intravenously via chronically implanted catheters. Blood samples were taken every 5 min for the first hour and then every 15 min for a further 3 h for the measurement of unlabeled and 3H-propranolol concentrations. During halothane anesthesia, intra-portal–intrinsic clearance was decreased by 62% (P < 0.05) from 2,110 ± 298 to 799 ± 233 ml/min, while systemic clearance was decreased (P < 0.05) from 470 ± 33 ml/min preanesthesia to 280 ± 38 ml/min during halothane anesthesia. The intravenous elimination half-life was increased (P < 0.05) from 87 ± 12 to 155 ± 23 min during anesthesia. Although halothane anesthesia tended to lower liver plasma flow from 642 ± 80 to 473 ± 47 ml/min, this change was not significant. The large change in portal or intrinsic clearance indicates that halothane anesthesia markedly inhibits drug-metabolizing ability. The authors therefore conclude that the alterations in drug disposition observed during halothane anesthesia are mainly due to inhibition of drug-metabolizing capacity in the liver.

Biochemical mechanisms of salicylate teratology in the rat.

Abstract Acetylsalicylic acid, salicylic acid and EDTA have been previously reported to be teratogenic in the rat, and such was confirmed in this study. However, neither the m- nor the p-isomers of salicylic acid, the analogs (neither an SH nor an NH2 group in place of OH, nor a CONH2 group in place of COOH), nor metabolites of salicylic acid were teratogenic. It is concluded that the teratogenic effect of aspirin is due to salicylic acid, its hydrolysis product, and that addition, shifting or substituting functional groups on the aromatic ring eliminates the teratogenic activity. The possibility that these teratogens act through mineral chelation was considered. The agents were administered by s.c. injection followed by 54Mn, 59Fe and 65Zn on day 9 or 16 of pregnancy in Sprague-Dawley rats. Measurements of urinary excretion and fetal uptake of the mineral isotopes were made at subsequent intervals. EDTA caused a marked increase in urinary excretion and a significant decrease in fetal uptake of all isotopes. Neither aspirin, salicylic acid, nor metabolites of aspirin, nor isomers, nor analogs of salicylic acid produced any significant alterations of mineral excretion or fetal uptake. It is postulated that while neither salicylic acid nor related compounds reduce fetal uptake of the minerals tested, they may still bind them in the maternal-fetal environment so that they are insufficiently available for normal biochemical functions of the developing fetus.

Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade.

To investigate the mechanisms of ventricular arrhythmia suppression by propranolol, we determined the antiarrhythmic efficacy of d-propranolol in 10 patients with frequent ventricular ectopic depolarizations (VEDs) and nonsustained ventricular tachycardia. After an initial placebo phase, 40 mg d-propranolol was administered orally every 6 h with dosage increased every 2 d until arrhythmia suppression (greater than or equal to 80% VED reduction), intolerable side effects, or a maximal dosage (1,280 mg/d) was reached. Response was verified by documenting return of arrhythmia during a final placebo phase. Arrhythmia suppression occurred in six patients while two more had partial responses. Effective dosages were 320-1,280 mg/d (mean 920 +/- 360, SD) of d-propranolol with corresponding plasma concentrations of 60-2,280 ng/ml (mean 858 +/- 681). For the entire group, the QTc interval shortened by 4 +/- 4% (P = 0.03). Arrhythmia suppression was accompanied by a reduction in peak heart rate during exercise of 0-29%. To determine whether arrhythmia suppression could be attributed to beta-blockade, racemic propranolol was then administered in dosages producing the same or greater depression of exercise heart rate. In 3/8 patients, arrhythmias were not suppressed by racemic propranolol indicating that d-propranolol was effective via a non-beta-mediated action. By contrast, in 5/8 patients racemic propranolol also suppressed VEDs. We conclude that propranolol suppresses ventricular arrhythmias by both beta- and non-beta-adrenergic receptor-mediated effects.

Studies on the metabolic fate of [14C]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the mouse.

Studies on the Metabolic Fate of [14C]2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in the Mouse. KOSHAKJI, R. P., HARBISON, R. D., and BUSH, M. T. (1984). Toxicol. Appl. Pharmacol. 73, 69-77. After a single po dose (135 micrograms/kg; 62 microCi/kg) of 14C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in male ICR/Ha Swiss mice, 67 to 76% of the administered dose was eliminated via the feces and 1 to 2% in the urine during the first 24 hr following treatment. It seems likely that most of this material was simply not absorbed. Much of the remaining chemical was then excreted slowly in the urine (2%) and feces (7%) during the next 10 days, partly as the unchanged compound and partly as metabolites. One of the metabolites (Fraction II) appears to be a single polar, acidic metabolite characterized in urine (0.4 +/- 0.1%) and feces (2.2 +/- 0.2%), and is also likely excreted as a glucuronide conjugate. The rest of the radioactivity was in the form of unchanged TCDD in the animal body (17 +/- 2%). Steady rates of decline in the concentrations of the 14C as well as of the unchanged TCDD were reached in the feces and urine after the fifth day following the administration of the chemical. Based on this steady rate, the half-life of the radioactivity in the body was approximately 20 days. Urine, feces, and whole body were analyzed by solvent extraction, 14C counting, thin-layer chromatography, and countercurrent distribution.

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.

Interindividual differences in β‐receptor density contribute to variability in response to β‐adrenoceptor antagonists

To determine the role of changes in receptor density and the considerable interindividual variability in the response to β‐adrenergic antagonists, we determined the relationship between the β‐blockade produced by propranolol and the β‐adrenergic receptor density (Bmax) in 16 healthy subjects who received 10, 20, 40, and 80 mg propranolol every 8 hours for 1 day at each dosage level. The extent of β‐blockade produced was assessed as the reduction in exercise tachycardia. The extent of β‐blockade correlated with pretreatment lymphocyte Bmax (30 mg/day: r = 0.6290, p < 0.05; 60 mg/day: r = 0.5279, p < 0.05; 120 mg/day: r = 0.5888, p < 0.01; 240 mg/day: r = 0.6783, p < 0.005). When the extent of β‐blockade was corrected for plasma propranolol concentrations, the correlation was further improved (30 mg/day: r = 0.7636, p < 0.001; 60 mg/day: r = 0.7218, p < 0.002; 120 mg/day: r = 0.7814, p < 0.001; 240 mg/day: r = 0.6899,/> < 0.005). We conclude that the density of β‐adrenergic receptors is one of the principal factors that control β‐receptor response to antagonists in human beings.

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 < 0.05) by the administration of debrisoquin. As predicted, the 4‐hydroxypropranolol partial metabolic clearance was significantly (p < 0.05) inhibited by debrisoquin. However, the side‐chain oxidation pathway, as measured by naphthoxylactic acid, was also significantly (p < 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 were also inhibited.