Hong‐Hao Zhou

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.

Stereoselective disposition of carvedilol is determined by CYP2D6

Carvedilol is a mixed α‐ and β‐adrenergic receptor antagonist that is administered as a racemic mixture. Although the two isomers are equally potent as ∝1‐blockers the S(−)‐isomer is principally responsible for the β blockade of carvedilol. To determine the role of pharmacogenetics in the metabolism of carvedilol we studied nine extensive metabolizers of both debrisoquin and mephenytoin, seven poor metabolizers of debrisoquin but extensive metabolizers of mephenytoin, and three poor metabolizers of mephenytoin but extensive metabolizers of debrisoquin. The clearance of R‐carvedilol was significantly lower than S‐carvedilol in both debrisoquin phenotypes. Poor metabolizers of debrisoquin had a significantly lower clearance of R‐carvedilol than extensive metabolizers of debrisoquin. The partial metabolic clearance of carvedilol to the two ring‐hydroxylated metabolites 4‐ and 5‐hydroxyphenyl carvedilol were significantly reduced in poor metabolizers of debrisoquin. No effect of mephenytoin phenotype on carvedilol kinetics was observed. Thus carvedilol is stereoselectively metabolized in humans, and the clearance of S‐carvedilol is higher than that of R‐carvedilol. In poor metabolizers of debrisoquin the clearance of R‐carvedilol is further reduced, resulting in higher plasma concentrations and perhaps greater α‐blockade.

Arg389Gly β1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo

There are marked interethnic differences in beta 1-adrenoceptor-mediated responsiveness, with sensitivity decreased in African-Americans and increased in Chinese compared with Caucasians. Therefore, the frequency of a common naturally occurring polymorphism of the human beta 1-adrenoceptor gene (Arg389Gly), which has functional importance in vitro, was determined in 194 African-Americans, 316 Caucasian-Americans, 221 Hispanic-Americans and 142 Chinese. African-Americans were found to have a significantly lower frequency of the Arg389 allele than the other three ethnic groups (all P < 0.01). In the populations studied, the order of the distribution of the Arg389 allele was: Chinese (74%) > Caucasians (72%) > Hispanics (67%) > African-Americans (58%). To determine the functional significance of the Arg389Gly beta 1-adrenoceptor polymorphism, in-vivo heart rate responses to exercise were compared in healthy subjects homozygous for the Arg (n = 9) and Gly (n = 8) alleles. Heart rate response to exercise was not affected by genotype (P = 0.4). Although ethnic differences in the frequency of the beta 1-adrenoceptor Arg389Gly polymorphism exist, the polymorphism does not appear to have functional significance in healthy subjects and therefore may not contribute to ethnic differences in response to drugs acting through the beta 1-adrenoceptor.

Ethnic differences in response to morphine

Only recently has attention been focused on the importance of interethnic differences as determinants of interindividual variability in drug response. We compared the pharmacokinetics and pharmacodynamics of morphine in eight Chinese and eight white healthy men after 0.15 mg/kg of morphine intravenously. The clearance of morphine was significantly higher in the Chinese subjects than in the white subjects because of an increase in the partial metabolic clearance by glucuronidation. There was no interethnic difference in the metabolism to normorphine. Morphine depressed the respiratory response to rebreathing carbon dioxide more in white subjects than in Chinese subjects, resulting in a greater reduction in resting ventilation and resting end‐tidal Pco2. The slope of the ventilation/Pco2 response curve, a measure of carbon dioxide sensitivity, was reduced more in white subjects than Chinese subjects. As a result, white subjects had a greater depression in ventilation at a Pco2 of 55 mm Hg. The morphine‐induced reduction in blood pressure was also greater in white subjects than in Chinese subjects. Thus this study has shown ethnicity to be an important determinant of the disposition and effects of morphine.

Differences in plasma binding of drugs between Caucasians and Chinese subjects

Interracial differences in drug responsiveness can be accounted for, at least in part, by differences in drug disposition. To investigate whether reversible interactions with plasma constituents may be a contributing factor in such differences, the binding of a number of model drugs was studied in plasma obtained from healthy Caucasian and Chinese subjects (n = 8 in each group). The unbound fractions of drugs binding to sites I and II on albumin (warfarin, diazepam, and salicylic acid) were similar in the two groups, and there was no difference in the plasma albumin concentration. By contrast, the percentages of unbound diphenhydramine (26.40% ± 6.46% versus 18.30% ± 4.31, mean ± SD) and propranolol (13.81% ± 1.33% versus 11.68% ± 2.37) were significantly (p < 0.05) higher in Chinese subjects compared to Caucasians. A 30% difference was also observed in the nonlinear binding of disopyramide. These basic drugs interact with both α1‐acid glycoprotein and albumin, and the lower binding was associated with a lower plasma concentration of the acute‐phase reactant in Chinese subjects. Kinetic analysis of the disopyramide binding isotherm was also suggestive of reduced binding capacity with no change in binding affinity. The reason for the racial difference in the α1‐acid glycoprotein level is unknown; however, for drugs extensively bound to this glycoprotein the resulting difference in unbound fraction would be expected to have predictable pharmacokinetic consequences that may result in differences in responsiveness. Determination of plasma binding, especially of drugs interacting with α1‐acid glycoprotein, should therefore be an essential component of comparative studies in subjects of different races.

Quinidine reduces clearance of (+)‐propranolol more than (−)‐propranolol through marked reduction in 4‐hydroxylation

Because both quinidine and propranolol bind to the cytochrome P‐450 responsible for the oxidation of debrisoquin, six healthy male subjects were studied to determine whether an interaction occurred between the two drugs and the pharmacodynamic consequences of that interaction. The coadministration of quinidine resulted in a doubling of the area under the plasma concentration—time curve of (±)‐propranolol (530 ± 99 versus 1051 ± 138 ng · hr/ml; p < 0.05) and a reduction in the clearance of (±)‐propranolol from 3087 ± 648 to 1378 ± 173 ml/min (p < 0.05). The metabolism of propranolol by the 4‐hydroxylation pathway was almost abolished by quinidine, resulting in a fall in the partial metabolic clearance by this pathway from 678 ± 246 to 56 ± 11 ml/min (p < 0.05). Quinidine differentially affected the metabolism of (+)‐propranolol and (−)‐propranolol, resulting in an increase of 176.6% ± 45.5% and 100.4% ± 25.5% in the area under the plasma concentration—time curve of (+)‐propranolol and (−)‐propranolol, respectively (p < 0.05). The pharmacokinetic changes were associated with pharmacodynamic effects. The combination of propranolol and quinidine resulted in increased ß‐blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals. We conclude that quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased β‐blockade.

Differences in stereoselective disposition of propranolol do not explain sensitivity differences between white and Chinese subjects: Correlation between the clearance of (−)‐ and (+)‐propranolol

We have previously demonstrated that Chinese subjects are more sensitive than white subjects to β‐blockade produced by propranolol. To determine if this difference was because a greater proportion of the total propranolol was the more active (−)‐isomer of propranolol in the Chinese subjects than in the white subjects, the relative pharmacokinetics of (+)‐ and (−)‐isomers of propranolol after administration of a single, 80 mg oral dose of racemic propranolol was studied in 10 Chinese male and in 9 white male healthy subjects. The plasma concentrations of both (+)‐ and (−)‐propranolol were lower in Chinese than in white subjects, resulting in significantly lower peak plasma concentrations and areas under the concentration‐time curve (AUC) in Chinese subjects, the half‐life of elimination did not differ significantly between Chinese and white subjects or between the two isomers. The concentrations of the active (−)‐propranolol were higher in both groups of subjects because of the lower clearance of the (−)‐propranolol compared with the (+)‐propranolol. An excellent correlation between the clearance of (+)‐ and (−)‐propranolol was seen in the same individual. The ratio of AUC of (−)‐ and (+)‐propranolol did not differ between Chinese subjects (0.64 ± 0.03) and white subjects (0.71 ± 0.09). The data suggest that the proportion of the two isomers found in Chinese and white subjects did not differ, and therefore differences in stereoselective disposition of propranolol cannot explain the increased sensitivity seen in Chinese individuals.

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.

Increased suppression of exercise‐induced increase in renin by propranolol in Chinese subjects

Sensitivity to the hypotensive effect of propranolol differs between Chinese subjects and white subjects. To explore the pharmacodynamic explanation for this difference, eight Chinese subjects (age range, 25 to 42 years) and eight white subjects (age range, 22 to 36 years) were given single doses of 10, 20, 40, and 80 mg propranolol on separate occasions at least 3 days apart. Heart rate, mean blood pressure, norepinephrine, epinephrine, and plasma renin activity were measured at the end of treadmill exercise 2 hours after medication was administered. Propranolol produced a concentration‐dependent reduction in mean blood pressure and heart rate in both groups. Concentration‐response curves were shifted significantly to the left in Chinese subjects, confirming the increased sensitivity to propranolol of the Chinese. The baseline exercise plasma renin activity was twofold higher (p < 0.05) in Chinese than in white subjects. The sensitivity to β‐blockade—induced suppression of plasma renin activity was increased in the Chinese, which resulted in a sevenfold higher concentration being required in white subjects than in Chinese to produce the same 50% suppression of exercise plasma renin activity (84.8 ± 23.2 versus 12.7 ± 7.4 ng/ml, p < 0.05). The reduction in exercise heart rate and mean blood pressure produced by propranolol were well correlated to the reduction in exercise plasma renin activity in both populations. There was no significant effect of either race or propranolol on plasma catecholamine concentration after exercise. The findings indicate that the previously demonstrated higher sensitivity to β‐blockade produced by propranolol also extends to the β ‐receptor—mediated effect on renin activity and this increased sensitivity to plasma renin activity suppression in Chinese subjects may partially explain their increased sensitivity to the hypotensive effects of propranolol.

Differing effect of atropine on heart rate in Chinese and white subjects

To determine if differences exist between Chinese and white subjects in their response to atropine and if the intrinsic heart rate and the autonomic contribution to the heart differ between the two races, eight white and eight Chinese males were studied. In all subjects the heart rate decreased after the first dose of atropine (0.003 mg/kg) with no difference in the bradycardia between the two races. However, as further doses were administered, the heart rate increased in both groups, resulting in a significantly (p < 0.05) greater increase in Chinese subjects than in white subjects. The increase in heart rate for each nanogram per milliliter of atropine was 2.8‐fold higher (p < 0.05) in the Chinese subjects (19.24 ± 4.41 beats/min) compared with white subjects (6.83 ± 1.62 beats/min). There was no difference in the intrinsic heart rate, in the relative vagal contribution, or in relative sympathetic contribution to the heart rate between the Chinese and white subjects. These data indicate that Chinese subjects are more sensitive to the effect of atropine, which is not related to the contribution of autonomic tone to the heart.