PERSPECTIVE Edited by Milo Gibaldi
REVISITING SOME FACTORS CONTRIBlYl1NG TO VARIABILITY Milo Gibaldi
Circadian Variation and Drug Therapy are terms used to describe a regular fluctuation in biologic function within a 24-~our period. Almost every physiologic variable having an mfluence on drug kinetics has been shown to exhibit cir~adian rhythm. A case in point is hepatic blood flow, which may be a major determinant in the clearance of lipophilic, rapidly metabolized drugs. Lemmer and Nold estimated the hepatic blood flow in ten healthy subjects maintained in the supine position, who were given single intravenous injections of indocyanine green (lCG) at 0800 and 2000 on one day and 0200 and 1400 on the next day. The investigators assumed that hepatic blood flow was inversely related to ICG half-life. The plasma half-life of ICG showed significant circadian variation; it was longest at 1400 (mean 3.5 min) and shortest at 0800 (mean 2.7 rnin). The hepatic blood flow at those times was estimated to be 1.14 and 1.54 Lrnin, respectively;' Postural changes, exercise,' and food' have also been found to alter hepatic blood flow. Olanoff et al. showed that the increase in hepatic blood flow following a meal leads to increased systemic clearance of propranolol, but a decreased first-pass effect after an oral dose." These findings of increased bioavailability with an increase in hepatic blood flow,' together with Lemmer and Nold's observation of a relativ~ly high ~epatic blood flow rate in the morning,' may explam why higher plasma concentrations of propranolol are observed when the drug is taken orally at 0800 than at other times of the day" and why plasma concentrations of nifedipine are higher in the morning than in the
CIRCADIAN AND DIURNAL RHYTHM
evening." GASTRIC EMPTYING AND DRUG ABSORPTION
. Cir~adi~ r~ythms have,been observed for drug absorpnon, distribution, metabolism, and excretion. Rhythms in the absorption of oral medication are probably secondary to circadian variation in food intake, posture, and activity. An example of systematic variation in drug absorption has been provided by De Mey and Meineke, who measured
MILO GIBALDI, Ph.D., is the Dean, School of Pharmacy, University of Washington, Seattle, WA 98915.
1002
•
The Annals ofPharmacotherapy
•
plasma concentrations of 5-aminosalicylic acid (5-ASA) in healthy men given 1.5-g doses of 5-ASA in enteric-coated tablets at 0700, 1400, and 2100, one hour before a standard meal on one day and immediately after a meal on a second day. Absorption of 5-ASA was relatively rapid only after the 0700 dose taken one hour before breakfast. The absorption of 5-ASA following all other doses, whether given before or after meals, was delayed. In both study periods, the 48-hour plasma concentration time profile following admini~tration of the first dose showed only two peak concentrations, even though three doses had been given. When the drug was given one hour before meals, peaks occurred 6 and 24 hours after the first dose; given after meals, 5-ASA peak concentrations were noted 12 and 24 hours after the first dose. In each case, the peak at 24 hours was much greater than the 12-hour peak? Determination of the area under the 5-ASA concentration time curve (AVC) for specific time segments of the 48-hour profile suggests that at least half the daily dose of enteric-coated 5-ASA is absorbed over a period ranging from 20 to 28 hours after the first dose. According to De Mey and Meineke, the sharp rise in the plasma concentrations of 5-ASA independent of when the tablets were taken with respect to meals suggests that tablets or tablet fragments remained in the stomach until the later part of the night or early morning, at which time they we~ rele~sed ~ather abruptly. "This would imply that only the interdigestive phase ill gastric contractions which occur specifically at this time of day were successful in emp~ing ~e s~omach of th~se large tablets whereas previous interdigestive phases faded. The lack of adequate 'interdigestive housekeeping' during the day may be a consequence of an effect of the intermittent snacks and meals in shortening the interdigestive phases."? SAFETY AND EFFICACY OF ANTICANCER AGENTS
The toxicity of some anticancer agents in rodents varies according to the time of day the drug is given. The clinical effects of some of these agents have also been shown to be dependent on the dosing schedule. A particularly striking example of this was provided by Hrushesky, who randomized women with ovarian cancer to one of two treatment schedules. In one, adriamycin was given at 0600 and cis-
1992 July/August. Volume 26
Downloaded from aop.sagepub.com at CORNELL UNIV on August 4, 2016
platin was given 12 hours later. In the other, cisplatin was given in the morning and adriamycin in the evening. The patients received at least eight monthly courses of each therapy and toxicity was evaluated after each course. The dose of adriamycin was reduced if an infection or bleeding complication had developed. Delays between the treatments were usually the result of slow recovery of blood cell counts. Treatment complications were defmed as clinical infections, bleeding episodes, and anemia requiring transfusion. The dose of adriamycin needed to be reduced and treatment delays were experienced in significantly more patients given adriamycin in the evening than in the morning. Even though patients treated with adriamycin in the evening received smaller doses, episodes of infection and bleeding were more common, and transfusion was required more often in these patients than in those given adriamycin in the morning. Hrushesky concluded that "this investigation indicates that circadian timing of administration of adriamycin and cisplatin, which are the two most commonly used anticancer drugs in the United States, intluences toxicity substantially.'" In the same vein, Rivard et al. hypothesized that "Given the important diurnal variations in DNA synthesis activity of normal blood-cell precursors as well as of leukaemic cells, it would not be surprising if the therapeutic index of 6-rnercaptopurine (6-MP) was intluenced by its schedule of administration. ''9 Seeking support for their hypothesis, Rivard et al. studied children with acute lymphoblastic leukemia who had achieved complete remission with standard chemotherapy and were receiving maintenance chemotherapy. The maintenance therapy consisted of daily administration of 6-MP and weekly administration of methotrexate (MTX), among other drugs. Eighty-two children received 6-MP and MTX in the morning and 18 received these agents in the evening. Patient characteristics were similar between the two groups, but disease-free survival proved to be better in children on evening chemotherapy than in those receiving morning treatment. For patients who survived for more than 78 weeks, the risk of relapse was nearly five times greater for the patients on the morning schedule than for those on the evening one.' Bone marrow toxicity is a dose-limiting factor for MTX and 6-MP. Normal bone marrow cells have minimum synthesis activity at night. ''Administration of MTX and 6-MP in the evening could therefore give normal cells an advantage over leukaemic cells which have minimal diurnal changes in DNA synthesis. Moreover, since normalleucocytes have their maximum dihydrofolic acid reductase activity at night, they could be protected against the toxic effect of MTX given at that time."? Another possibility for the improved outcomes when chemotherapy was given in the evening is higher blood concentrations of the antitumor agents. This has been documented for 6-MP by Langevin et al., who found a significantly larger AUC and a longer elimination half-life in children who received the drug at night." Because 6-MP was used in combination with MTX, might higher concentrations of MTX in the evening also contribute to improved outcomes? This question was studied by Ferrazzini et al. in children with leukemia. They found a significant fall in MTX plasma clearance at night as a result of decreased renal clearance. Hence, systemic exposure to MTX is also greater at night than during the day. The most dramatic di-
urnal difference was seen in the unbound renal clearance of MTX, which averaged 17.5 mL min:' kg" during the day and 8.5 mL min- I kg" at night. The glomerular filtration rate (GFR) estimated from creatinine clearance did not exhibit diurnal variation, but there was a considerable decrease in the nonglomerular clearance of MTX at night (unbound renal clearance minus GFR, 0.098 vs. 0.051). Ferrazzini et al. pointed out that "the changes in methotrexate clearance carmot be attributed to diurnal variability in GFR, but rather to a reduction in its tubular secretion. Since it is a weak organic acid, the tubular reabsorption of methotrexate depends on urinary pH. At night, urinary pH tends to be more acidic and this may result in more reabsorption of the less ionized drug and hence reduced renal clearance. "11 In another report, investigators described the use of an implantable pump delivering a continuous intravenous infusion of 5-tluoro-2-deoxyuridine (FUDR) in 14-day cycles alternating with 14-day intervals of heparinized physiologic saline infusion to patients with metastatic renal cell carcinoma (RCC).12 FUDR was infused according to the circadian rhythm described by Hrushesky et al., which is based on evidence suggesting that FUDR is least toxic in the late afternoon and evening"; 68 percent of the daily dose was given between 1500 and 2100, 15 percent between 2100 and 0300, 2 percent between 0300 and 0900, and 15 percent between 0900 and 1500. Based on their findings, Damascelli et al. concluded: "Despite the organizational problems and the initial costs, we believe that the circadian continuous infusion of FUDR for the control of metastatic RCC should be encouraged.... This therapy is as active as any currently available treatment, is administered in an entirely outpatient setting, and is associated with a normal quality of life."? The idea of taking body rhythms into account when developing therapeutic strategies has also attracted attention from the popular media. The New York Times described a patient with kidney cancer who received a six-hour infusion of an anticancer agent at 2100 each night. "By timing the drug infusion for the part of the day when intestinal cells divide slowly, Mr. Wynn's doctors have avoided provoking the diarrhea that usually limits the cancer drug's
use.'?" CARDIOVASCULAR DISEASE
Muller and Totler have observed: "A morning increase in the risk of acute cardiovascular disorders-transient myocardial ischemia, myocardial infarction, sudden cardiac death, and stroke-is now well documented and widely accepted by both the medical profession and the public.'?" Panza et al. pointed out that a similar rhythm has been seen in several pertinent physiologic processes. "Blood fibrinolytic activity is lower in the early morning hours and platelet aggregability, plasma epinephrine and norepinephrine levels, plasma renin activity, and the rate of cortisol secretion are higher. "16 Muller et al. linked the circadian rhythm in these variables with epidemiologic evidence to support the view that "certain dynamic physiologic mechanisms contribute to, and even trigger, the onset of acute cardiovascular events."? Circadian variation may also affect vascular tone. Panza et al. convincingly demonstrated in healthy subjects that forearm vascular resistance, as determined by plethysmog-
The Annals ofPharmacotherapy
•
Downloaded from aop.sagepub.com at CORNELL UNIV on August 4, 2016
1992 July/August. Volume 26
•
1003
raphy, is higher in the morning than at other times of the day. They also determined that the increased resistance was attributable to alpha-adrenergic activity, as it was abolished by intraarterial administration of phentolamine, an alpha-adrenergic blocker. The investigators suggested that this variation "may contribute to higher blood pressure and the increased incidence of cardiovascular events at this time of day."16 In an editorial accompanying Panza et al. 's report, Muller and Tofler observed: "The most exciting aspect of the knowledge gained thus far about the timing of the onset of cardiovascular events is the potential for extending recent progress in the treatment of the disease to include prevention-an essential step, because most cardiac deaths occur before treatment can be given .... A challenge for the future is to add to the knowledge gained in studies of thrombolysis an increased understanding of what happens in the crucial moments before the rupture of a plaque and the formation of an occlusive thrombus." They went on to point out: "Understanding the mechanism of cardiovascular events would arm the medical profession with new power to confront the largest part of the mortality caused by cardiovascular disease. Efforts to reduce acute risk factors could be added to the measures taken to reduce chronic risk factors ... that have already been successful in prevention. In some cases, acute risk may best be prevented by eliminating the potential trigger, such as involvement in strenuous exertion without previous conditioning. In the case of unavoidable activity, drugs or other treatment could be used to sever the link between a triggering process and a lethal outcome. "15
Drugs in the Elderly PHARMACOKINETIC CONSIDERATIONS
A number of changes in hepatic function occur with aging, including a decrease in liver size, diminished number and function of hepatocytes, decreased hepatic blood flow, and lower drug metabolizing ability. These changes may lead to higher blood concentrations and adverse effects of drugs in the elderly. For example, a decrease in drug metabolizing ability has been shown to account for increased plasma propranolol concentrations in elderly patients with hypertension. IS With propranolol, however, there is little concern over safety because the elevated concentrations in the elderly seem to be offset by a decreased sensitivity to beta-blockers." Propranolol is a racemic mixture and its two enantiomers differ with respect to pharmacokinetics and betablocker activity. The clearance of (+ )-propranolol is greater than that of (-j-propranolol" and (-)-propranolol is at least 100 times more potent than (+ )-propranolopl A substantial effect of age on the stereoselective disposition of hexobarbital" and mephobarbital-' has been reported. Is it possible that the age-related decrease in propranolol clearance does not affect both isomers to the same extent and that the decreased sensitivity to propranolol in the elderly is due to a relatively greater increase in the plasma concentrations of the less active (+ )-enantiomer? To answer that question, Zhou et al. investigated the effect of age on the oral clearance of (-)- and (+ )-propranolol in six young (aged 24-32 y) and six elderly (aged 65-80 y) healthy men. Each subject was given a single 80-mg oral
1004 •
The Annals ofPharmacotherapy •
dose of racemic propranolol. Consistent with earlier reports, the mean peak plasma concentrations of both (+)and (-)-propranolol were significantly higher and the mean oral clearances of both enantiomers were significantly lower in the elderly than in the young subjects. Stereoselective metabolism of propranolol was observed in both young and elderly subjects. In each group, the oral clearance of the (+ )-enantiomer was about 50 percent greater than that of the (-)-enantiomer. Furthermore, in the study panel as a whole, the oral clearance of (+ )-propranolol was highly correlated with that of (-)-propranolol (r=0.86, p
REVISITING SOME FACTORS CONTRIBlYl1NG TO VARIABILITY Milo Gibaldi
Circadian Variation and Drug Therapy are terms used to describe a regular fluctuation in biologic function within a 24-~our period. Almost every physiologic variable having an mfluence on drug kinetics has been shown to exhibit cir~adian rhythm. A case in point is hepatic blood flow, which may be a major determinant in the clearance of lipophilic, rapidly metabolized drugs. Lemmer and Nold estimated the hepatic blood flow in ten healthy subjects maintained in the supine position, who were given single intravenous injections of indocyanine green (lCG) at 0800 and 2000 on one day and 0200 and 1400 on the next day. The investigators assumed that hepatic blood flow was inversely related to ICG half-life. The plasma half-life of ICG showed significant circadian variation; it was longest at 1400 (mean 3.5 min) and shortest at 0800 (mean 2.7 rnin). The hepatic blood flow at those times was estimated to be 1.14 and 1.54 Lrnin, respectively;' Postural changes, exercise,' and food' have also been found to alter hepatic blood flow. Olanoff et al. showed that the increase in hepatic blood flow following a meal leads to increased systemic clearance of propranolol, but a decreased first-pass effect after an oral dose." These findings of increased bioavailability with an increase in hepatic blood flow,' together with Lemmer and Nold's observation of a relativ~ly high ~epatic blood flow rate in the morning,' may explam why higher plasma concentrations of propranolol are observed when the drug is taken orally at 0800 than at other times of the day" and why plasma concentrations of nifedipine are higher in the morning than in the
CIRCADIAN AND DIURNAL RHYTHM
evening." GASTRIC EMPTYING AND DRUG ABSORPTION
. Cir~adi~ r~ythms have,been observed for drug absorpnon, distribution, metabolism, and excretion. Rhythms in the absorption of oral medication are probably secondary to circadian variation in food intake, posture, and activity. An example of systematic variation in drug absorption has been provided by De Mey and Meineke, who measured
MILO GIBALDI, Ph.D., is the Dean, School of Pharmacy, University of Washington, Seattle, WA 98915.
1002
•
The Annals ofPharmacotherapy
•
plasma concentrations of 5-aminosalicylic acid (5-ASA) in healthy men given 1.5-g doses of 5-ASA in enteric-coated tablets at 0700, 1400, and 2100, one hour before a standard meal on one day and immediately after a meal on a second day. Absorption of 5-ASA was relatively rapid only after the 0700 dose taken one hour before breakfast. The absorption of 5-ASA following all other doses, whether given before or after meals, was delayed. In both study periods, the 48-hour plasma concentration time profile following admini~tration of the first dose showed only two peak concentrations, even though three doses had been given. When the drug was given one hour before meals, peaks occurred 6 and 24 hours after the first dose; given after meals, 5-ASA peak concentrations were noted 12 and 24 hours after the first dose. In each case, the peak at 24 hours was much greater than the 12-hour peak? Determination of the area under the 5-ASA concentration time curve (AVC) for specific time segments of the 48-hour profile suggests that at least half the daily dose of enteric-coated 5-ASA is absorbed over a period ranging from 20 to 28 hours after the first dose. According to De Mey and Meineke, the sharp rise in the plasma concentrations of 5-ASA independent of when the tablets were taken with respect to meals suggests that tablets or tablet fragments remained in the stomach until the later part of the night or early morning, at which time they we~ rele~sed ~ather abruptly. "This would imply that only the interdigestive phase ill gastric contractions which occur specifically at this time of day were successful in emp~ing ~e s~omach of th~se large tablets whereas previous interdigestive phases faded. The lack of adequate 'interdigestive housekeeping' during the day may be a consequence of an effect of the intermittent snacks and meals in shortening the interdigestive phases."? SAFETY AND EFFICACY OF ANTICANCER AGENTS
The toxicity of some anticancer agents in rodents varies according to the time of day the drug is given. The clinical effects of some of these agents have also been shown to be dependent on the dosing schedule. A particularly striking example of this was provided by Hrushesky, who randomized women with ovarian cancer to one of two treatment schedules. In one, adriamycin was given at 0600 and cis-
1992 July/August. Volume 26
Downloaded from aop.sagepub.com at CORNELL UNIV on August 4, 2016
platin was given 12 hours later. In the other, cisplatin was given in the morning and adriamycin in the evening. The patients received at least eight monthly courses of each therapy and toxicity was evaluated after each course. The dose of adriamycin was reduced if an infection or bleeding complication had developed. Delays between the treatments were usually the result of slow recovery of blood cell counts. Treatment complications were defmed as clinical infections, bleeding episodes, and anemia requiring transfusion. The dose of adriamycin needed to be reduced and treatment delays were experienced in significantly more patients given adriamycin in the evening than in the morning. Even though patients treated with adriamycin in the evening received smaller doses, episodes of infection and bleeding were more common, and transfusion was required more often in these patients than in those given adriamycin in the morning. Hrushesky concluded that "this investigation indicates that circadian timing of administration of adriamycin and cisplatin, which are the two most commonly used anticancer drugs in the United States, intluences toxicity substantially.'" In the same vein, Rivard et al. hypothesized that "Given the important diurnal variations in DNA synthesis activity of normal blood-cell precursors as well as of leukaemic cells, it would not be surprising if the therapeutic index of 6-rnercaptopurine (6-MP) was intluenced by its schedule of administration. ''9 Seeking support for their hypothesis, Rivard et al. studied children with acute lymphoblastic leukemia who had achieved complete remission with standard chemotherapy and were receiving maintenance chemotherapy. The maintenance therapy consisted of daily administration of 6-MP and weekly administration of methotrexate (MTX), among other drugs. Eighty-two children received 6-MP and MTX in the morning and 18 received these agents in the evening. Patient characteristics were similar between the two groups, but disease-free survival proved to be better in children on evening chemotherapy than in those receiving morning treatment. For patients who survived for more than 78 weeks, the risk of relapse was nearly five times greater for the patients on the morning schedule than for those on the evening one.' Bone marrow toxicity is a dose-limiting factor for MTX and 6-MP. Normal bone marrow cells have minimum synthesis activity at night. ''Administration of MTX and 6-MP in the evening could therefore give normal cells an advantage over leukaemic cells which have minimal diurnal changes in DNA synthesis. Moreover, since normalleucocytes have their maximum dihydrofolic acid reductase activity at night, they could be protected against the toxic effect of MTX given at that time."? Another possibility for the improved outcomes when chemotherapy was given in the evening is higher blood concentrations of the antitumor agents. This has been documented for 6-MP by Langevin et al., who found a significantly larger AUC and a longer elimination half-life in children who received the drug at night." Because 6-MP was used in combination with MTX, might higher concentrations of MTX in the evening also contribute to improved outcomes? This question was studied by Ferrazzini et al. in children with leukemia. They found a significant fall in MTX plasma clearance at night as a result of decreased renal clearance. Hence, systemic exposure to MTX is also greater at night than during the day. The most dramatic di-
urnal difference was seen in the unbound renal clearance of MTX, which averaged 17.5 mL min:' kg" during the day and 8.5 mL min- I kg" at night. The glomerular filtration rate (GFR) estimated from creatinine clearance did not exhibit diurnal variation, but there was a considerable decrease in the nonglomerular clearance of MTX at night (unbound renal clearance minus GFR, 0.098 vs. 0.051). Ferrazzini et al. pointed out that "the changes in methotrexate clearance carmot be attributed to diurnal variability in GFR, but rather to a reduction in its tubular secretion. Since it is a weak organic acid, the tubular reabsorption of methotrexate depends on urinary pH. At night, urinary pH tends to be more acidic and this may result in more reabsorption of the less ionized drug and hence reduced renal clearance. "11 In another report, investigators described the use of an implantable pump delivering a continuous intravenous infusion of 5-tluoro-2-deoxyuridine (FUDR) in 14-day cycles alternating with 14-day intervals of heparinized physiologic saline infusion to patients with metastatic renal cell carcinoma (RCC).12 FUDR was infused according to the circadian rhythm described by Hrushesky et al., which is based on evidence suggesting that FUDR is least toxic in the late afternoon and evening"; 68 percent of the daily dose was given between 1500 and 2100, 15 percent between 2100 and 0300, 2 percent between 0300 and 0900, and 15 percent between 0900 and 1500. Based on their findings, Damascelli et al. concluded: "Despite the organizational problems and the initial costs, we believe that the circadian continuous infusion of FUDR for the control of metastatic RCC should be encouraged.... This therapy is as active as any currently available treatment, is administered in an entirely outpatient setting, and is associated with a normal quality of life."? The idea of taking body rhythms into account when developing therapeutic strategies has also attracted attention from the popular media. The New York Times described a patient with kidney cancer who received a six-hour infusion of an anticancer agent at 2100 each night. "By timing the drug infusion for the part of the day when intestinal cells divide slowly, Mr. Wynn's doctors have avoided provoking the diarrhea that usually limits the cancer drug's
use.'?" CARDIOVASCULAR DISEASE
Muller and Totler have observed: "A morning increase in the risk of acute cardiovascular disorders-transient myocardial ischemia, myocardial infarction, sudden cardiac death, and stroke-is now well documented and widely accepted by both the medical profession and the public.'?" Panza et al. pointed out that a similar rhythm has been seen in several pertinent physiologic processes. "Blood fibrinolytic activity is lower in the early morning hours and platelet aggregability, plasma epinephrine and norepinephrine levels, plasma renin activity, and the rate of cortisol secretion are higher. "16 Muller et al. linked the circadian rhythm in these variables with epidemiologic evidence to support the view that "certain dynamic physiologic mechanisms contribute to, and even trigger, the onset of acute cardiovascular events."? Circadian variation may also affect vascular tone. Panza et al. convincingly demonstrated in healthy subjects that forearm vascular resistance, as determined by plethysmog-
The Annals ofPharmacotherapy
•
Downloaded from aop.sagepub.com at CORNELL UNIV on August 4, 2016
1992 July/August. Volume 26
•
1003
raphy, is higher in the morning than at other times of the day. They also determined that the increased resistance was attributable to alpha-adrenergic activity, as it was abolished by intraarterial administration of phentolamine, an alpha-adrenergic blocker. The investigators suggested that this variation "may contribute to higher blood pressure and the increased incidence of cardiovascular events at this time of day."16 In an editorial accompanying Panza et al. 's report, Muller and Tofler observed: "The most exciting aspect of the knowledge gained thus far about the timing of the onset of cardiovascular events is the potential for extending recent progress in the treatment of the disease to include prevention-an essential step, because most cardiac deaths occur before treatment can be given .... A challenge for the future is to add to the knowledge gained in studies of thrombolysis an increased understanding of what happens in the crucial moments before the rupture of a plaque and the formation of an occlusive thrombus." They went on to point out: "Understanding the mechanism of cardiovascular events would arm the medical profession with new power to confront the largest part of the mortality caused by cardiovascular disease. Efforts to reduce acute risk factors could be added to the measures taken to reduce chronic risk factors ... that have already been successful in prevention. In some cases, acute risk may best be prevented by eliminating the potential trigger, such as involvement in strenuous exertion without previous conditioning. In the case of unavoidable activity, drugs or other treatment could be used to sever the link between a triggering process and a lethal outcome. "15
Drugs in the Elderly PHARMACOKINETIC CONSIDERATIONS
A number of changes in hepatic function occur with aging, including a decrease in liver size, diminished number and function of hepatocytes, decreased hepatic blood flow, and lower drug metabolizing ability. These changes may lead to higher blood concentrations and adverse effects of drugs in the elderly. For example, a decrease in drug metabolizing ability has been shown to account for increased plasma propranolol concentrations in elderly patients with hypertension. IS With propranolol, however, there is little concern over safety because the elevated concentrations in the elderly seem to be offset by a decreased sensitivity to beta-blockers." Propranolol is a racemic mixture and its two enantiomers differ with respect to pharmacokinetics and betablocker activity. The clearance of (+ )-propranolol is greater than that of (-j-propranolol" and (-)-propranolol is at least 100 times more potent than (+ )-propranolopl A substantial effect of age on the stereoselective disposition of hexobarbital" and mephobarbital-' has been reported. Is it possible that the age-related decrease in propranolol clearance does not affect both isomers to the same extent and that the decreased sensitivity to propranolol in the elderly is due to a relatively greater increase in the plasma concentrations of the less active (+ )-enantiomer? To answer that question, Zhou et al. investigated the effect of age on the oral clearance of (-)- and (+ )-propranolol in six young (aged 24-32 y) and six elderly (aged 65-80 y) healthy men. Each subject was given a single 80-mg oral
1004 •
The Annals ofPharmacotherapy •
dose of racemic propranolol. Consistent with earlier reports, the mean peak plasma concentrations of both (+)and (-)-propranolol were significantly higher and the mean oral clearances of both enantiomers were significantly lower in the elderly than in the young subjects. Stereoselective metabolism of propranolol was observed in both young and elderly subjects. In each group, the oral clearance of the (+ )-enantiomer was about 50 percent greater than that of the (-)-enantiomer. Furthermore, in the study panel as a whole, the oral clearance of (+ )-propranolol was highly correlated with that of (-)-propranolol (r=0.86, p
