MEDLINE Abstracts: Drug Metabolism and Gender
MEDLINE Abstracts: Drug Metabolism and Gender
What's the latest in gender-based differences affecting drug metabolism? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pharmacotherapy.
Lackner TE, Cloyd JC, Thomas LW, et al
Epilepsia. 1998;39(10) p1083-7
Purpose: Examine antiepileptic drug (AED) use in nursing homes by age, gender, and use of comedication that can interact with AEDs.
Methods: Two point-prevalence evaluations of AED use from computerized medical records of nursing home residents throughout the United States (set 1, 43,757; set 2, 41,386) 65 years and older serviced by PHARMERICA.
Results: 10.5% of residents received an AED. Of the age group 65-84 years, 15 % received an AED compared with 6.1% of those 85 years or older (p < 0.001). Gender differences were present; 13.4% of the male residents and 9.4% of the female residents were treated with an AED (p < 0.001). The most frequently prescribed AEDs were phenytoin, carbamazepine, clonazepam, or phenobarbital. The average number of routine medications taken by AED recipients was 5.6, greater than the average of 4.6 for other residents.
Conclusions: AEDs are extensively prescribed for elderly nursing home residents. Men and persons aged 65-85 years were more likely to receive AEDs than were women or those older than 85 years. AED recipients receive more routine medications than do other residents, including co-medications that alter hepatic metabolism and clinical response. The reasons for age and gender differences are unclear and require further study.
Krecic-Shepard ME, Barnas CR, Slimko J, et al
Clin Pharmacol Ther. 2000; 68(3) p286-92
Pharmacokinetic studies after administration of 120 mg oral sustained- and regular-release racemic verapamil were performed in 13 healthy subjects (seven men, age 74 +/- 4 years [mean +/- SD], weight 69.9 +/- 5.4 kg, and body mass index 24.6 +/- 2.2]; and six women, age 65 +/- 13 years, weight 65 +/- 9.9 kg, and body mass index 25.3 +/- 3). Verapamil was measured by HPLC, concentration versus time data analyzed by noncompartmental models, and statistical analyses performed by ANOVA for repeated measurements. The area under the concentration versus time curve (AUC) after administration of sustained-release verapamil was 48,951 +/- 18,079 ng/mL x min(-1) in women compared with 25,595 +/- 10,245 in men and lower than after administration of regular-release verapamil (63,055 +/- 24,411 for women and 34,686 +/- 25,279 in men; P = .05 for sex-related effect and P < .02 for formulation effect). AUC ratios of norverapamil (N-demethylated metabolite) to verapamil after administration of sustained-release verapamil were 1.43 +/- 0.26 in women compared with 1.74 +/- 0.41 in men and 1.43 +/- 0.26 in women compared with 1.78 +/- 0.37 in men after administration of regular-release verapamil (P = .1 for sex-related effect and P = .9 for formulation effect). Apparent oral clearance was 43 +/- 15 mL/min/kg in women compared with 75 +/- 29 in men after administration of sustained-release verapamil and 35 +/- 16 mL/min/kg in women compared with 65 +/- 31 in men after administration of regular-release verapamil (P < .05 for sex-related effect and P < .02 for formulation effect). Apparent oral clearance of both regular- and sustained-release formulations of verapamil was faster in men compared with women in contrast to findings after intravenous administration of verapamil, suggesting that intestinal processes are a factor in sex-specific difference in drug clearance. Greater verapamil and norverapamil bioavailability after administration of regular- compared with sustained-release verapamil also suggests saturable processes at the intestinal level.
Gandhi SK, Gainer J, King D, et al
Hypertension. 1998;31(1) p90-6
This study tested the hypothesis that gender affects the pressor and renal vasoconstrictor responses to angiotensin (Ang) I and Ang II in salt-replete normotensive subjects. Ang I and Ang II were infused in graded doses into 9 men and 8 women in a randomized, single-blind, crossover study. There were no differences between genders in baseline blood pressure, heart rate, sodium excretion, renal plasma flow, angiotensin-converting enzyme (ACE) genotype, ACE activity, plasma renin activity, aldosterone, or Ang II levels. Although pressor responses to Ang I and Ang II were similar in men and women, there was a negative relationship between the change in mean arterial pressure and the change in heart rate during Ang I and II infusion in women only. The half-time of the pressor response after discontinuation of Ang I but not Ang II infusion was greater in men than in women (9.5+/-2.2 versus 4.3+/-2.1 minutes, P<.05). This difference in duration did not result from gender differences in the metabolism of Ang I because Ang II levels measured during Ang I infusion were identical in men and women. In contrast, the renal vasoconstrictor response to Ang I and Ang II was significantly increased in women compared with that in men (Ang I, -243+/-31 versus -138+/-13 U/1.73 m2; Ang II, -233+/-25 versus -175+/-18 U/1.73 m2; P<.03). These data suggest an effect of gender on baroreflex reactivity during angiotensin infusion. Moreover, in the setting of similar Ang II concentrations, the dramatic difference in the renal vasoconstrictor responses to Ang I and Ang II between salt-replete men and salt-replete women suggests gender differences at a pharmacodynamic level.
Benton RE, Sale M, Flockhart DA, et al
Clin Pharmacol Ther. 2000; 67(4) p413-8
Background: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women.
Methods: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2).
Results: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval.
Conclusions: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.
Xue FS, An G, Liao X, et al
Anesth Analg. 1998; 86(6) p1322-7
To evaluate the effect of gender on the pharmacokinetics of vecuronium, we studied 30 patients (15 male and 15 female) undergoing elective plastic surgery with anticipated surgical blood loss of <300 mL under general anesthesia. General anesthesia was induced with thiopental 4-6 mg/kg and fentanyl 2-4 microg/kg and was maintained with 60% nitrous oxide in oxygen and an end-tidal concentration of 1.5%-2% enflurane. After a 2-min infusion of vecuronium 100 microg/kg, a modified fluorometric assay was used to determine the plasma concentrations of vecuronium for 5 h. The results showed that, compared with women, the plasma concentrations of vecuronium in men were significantly lower during the first 20 min and that the disposition kinetics of vecuronium can be best described mathematically by a three-compartment open model in the two groups. The volume of the central compartment and the volume of distribution at steady state were 39.6 +/- 8.6 and 164.8 +/- 29.3 mL/kg, respectively, in women. These values increased significantly to 54.4 +/- 14.4 and 201.4 +/- 75.8 mL/kg in men (P < 0.05). When the data were calculated on the basis of ideal body weight, the volume of distribution of vecuronium was also different between men and women (P < 0.05. The half-lives of fast distribution and distribution, the elimination half-life, mean residual time, area under the plasma-concentration curve, and plasma clearance were not different between the two groups. We conclude that the pharmacokinetics of vecuronium are significantly different between genders and that and men have the greater volume of distribution of vecuronium. Implications: The authors found that, compared with women, men had lower plasma concentrations of vecuronium after the i.v. administration of vecuronium and a larger volume of distribution of vecuronium. The pharmacokinetic differences may be related to the differences in the sensitivity to vecuronium between genders.
Luzier AB, Killian A, Wilton JH, et al
Clin Pharmacol Ther. 1999;66(6) p594-601
Objective: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers.
Methods: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled.
Results: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20).
Conclusions: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.
Gear RW, Miaskowski C, Gordon NC, et al
Pain. 1999;83(2) p339-45
Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.
What's the latest in gender-based differences affecting drug metabolism? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pharmacotherapy.
Lackner TE, Cloyd JC, Thomas LW, et al
Epilepsia. 1998;39(10) p1083-7
Purpose: Examine antiepileptic drug (AED) use in nursing homes by age, gender, and use of comedication that can interact with AEDs.
Methods: Two point-prevalence evaluations of AED use from computerized medical records of nursing home residents throughout the United States (set 1, 43,757; set 2, 41,386) 65 years and older serviced by PHARMERICA.
Results: 10.5% of residents received an AED. Of the age group 65-84 years, 15 % received an AED compared with 6.1% of those 85 years or older (p < 0.001). Gender differences were present; 13.4% of the male residents and 9.4% of the female residents were treated with an AED (p < 0.001). The most frequently prescribed AEDs were phenytoin, carbamazepine, clonazepam, or phenobarbital. The average number of routine medications taken by AED recipients was 5.6, greater than the average of 4.6 for other residents.
Conclusions: AEDs are extensively prescribed for elderly nursing home residents. Men and persons aged 65-85 years were more likely to receive AEDs than were women or those older than 85 years. AED recipients receive more routine medications than do other residents, including co-medications that alter hepatic metabolism and clinical response. The reasons for age and gender differences are unclear and require further study.
Krecic-Shepard ME, Barnas CR, Slimko J, et al
Clin Pharmacol Ther. 2000; 68(3) p286-92
Pharmacokinetic studies after administration of 120 mg oral sustained- and regular-release racemic verapamil were performed in 13 healthy subjects (seven men, age 74 +/- 4 years [mean +/- SD], weight 69.9 +/- 5.4 kg, and body mass index 24.6 +/- 2.2]; and six women, age 65 +/- 13 years, weight 65 +/- 9.9 kg, and body mass index 25.3 +/- 3). Verapamil was measured by HPLC, concentration versus time data analyzed by noncompartmental models, and statistical analyses performed by ANOVA for repeated measurements. The area under the concentration versus time curve (AUC) after administration of sustained-release verapamil was 48,951 +/- 18,079 ng/mL x min(-1) in women compared with 25,595 +/- 10,245 in men and lower than after administration of regular-release verapamil (63,055 +/- 24,411 for women and 34,686 +/- 25,279 in men; P = .05 for sex-related effect and P < .02 for formulation effect). AUC ratios of norverapamil (N-demethylated metabolite) to verapamil after administration of sustained-release verapamil were 1.43 +/- 0.26 in women compared with 1.74 +/- 0.41 in men and 1.43 +/- 0.26 in women compared with 1.78 +/- 0.37 in men after administration of regular-release verapamil (P = .1 for sex-related effect and P = .9 for formulation effect). Apparent oral clearance was 43 +/- 15 mL/min/kg in women compared with 75 +/- 29 in men after administration of sustained-release verapamil and 35 +/- 16 mL/min/kg in women compared with 65 +/- 31 in men after administration of regular-release verapamil (P < .05 for sex-related effect and P < .02 for formulation effect). Apparent oral clearance of both regular- and sustained-release formulations of verapamil was faster in men compared with women in contrast to findings after intravenous administration of verapamil, suggesting that intestinal processes are a factor in sex-specific difference in drug clearance. Greater verapamil and norverapamil bioavailability after administration of regular- compared with sustained-release verapamil also suggests saturable processes at the intestinal level.
Gandhi SK, Gainer J, King D, et al
Hypertension. 1998;31(1) p90-6
This study tested the hypothesis that gender affects the pressor and renal vasoconstrictor responses to angiotensin (Ang) I and Ang II in salt-replete normotensive subjects. Ang I and Ang II were infused in graded doses into 9 men and 8 women in a randomized, single-blind, crossover study. There were no differences between genders in baseline blood pressure, heart rate, sodium excretion, renal plasma flow, angiotensin-converting enzyme (ACE) genotype, ACE activity, plasma renin activity, aldosterone, or Ang II levels. Although pressor responses to Ang I and Ang II were similar in men and women, there was a negative relationship between the change in mean arterial pressure and the change in heart rate during Ang I and II infusion in women only. The half-time of the pressor response after discontinuation of Ang I but not Ang II infusion was greater in men than in women (9.5+/-2.2 versus 4.3+/-2.1 minutes, P<.05). This difference in duration did not result from gender differences in the metabolism of Ang I because Ang II levels measured during Ang I infusion were identical in men and women. In contrast, the renal vasoconstrictor response to Ang I and Ang II was significantly increased in women compared with that in men (Ang I, -243+/-31 versus -138+/-13 U/1.73 m2; Ang II, -233+/-25 versus -175+/-18 U/1.73 m2; P<.03). These data suggest an effect of gender on baroreflex reactivity during angiotensin infusion. Moreover, in the setting of similar Ang II concentrations, the dramatic difference in the renal vasoconstrictor responses to Ang I and Ang II between salt-replete men and salt-replete women suggests gender differences at a pharmacodynamic level.
Benton RE, Sale M, Flockhart DA, et al
Clin Pharmacol Ther. 2000; 67(4) p413-8
Background: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women.
Methods: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2).
Results: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval.
Conclusions: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.
Xue FS, An G, Liao X, et al
Anesth Analg. 1998; 86(6) p1322-7
To evaluate the effect of gender on the pharmacokinetics of vecuronium, we studied 30 patients (15 male and 15 female) undergoing elective plastic surgery with anticipated surgical blood loss of <300 mL under general anesthesia. General anesthesia was induced with thiopental 4-6 mg/kg and fentanyl 2-4 microg/kg and was maintained with 60% nitrous oxide in oxygen and an end-tidal concentration of 1.5%-2% enflurane. After a 2-min infusion of vecuronium 100 microg/kg, a modified fluorometric assay was used to determine the plasma concentrations of vecuronium for 5 h. The results showed that, compared with women, the plasma concentrations of vecuronium in men were significantly lower during the first 20 min and that the disposition kinetics of vecuronium can be best described mathematically by a three-compartment open model in the two groups. The volume of the central compartment and the volume of distribution at steady state were 39.6 +/- 8.6 and 164.8 +/- 29.3 mL/kg, respectively, in women. These values increased significantly to 54.4 +/- 14.4 and 201.4 +/- 75.8 mL/kg in men (P < 0.05). When the data were calculated on the basis of ideal body weight, the volume of distribution of vecuronium was also different between men and women (P < 0.05. The half-lives of fast distribution and distribution, the elimination half-life, mean residual time, area under the plasma-concentration curve, and plasma clearance were not different between the two groups. We conclude that the pharmacokinetics of vecuronium are significantly different between genders and that and men have the greater volume of distribution of vecuronium. Implications: The authors found that, compared with women, men had lower plasma concentrations of vecuronium after the i.v. administration of vecuronium and a larger volume of distribution of vecuronium. The pharmacokinetic differences may be related to the differences in the sensitivity to vecuronium between genders.
Luzier AB, Killian A, Wilton JH, et al
Clin Pharmacol Ther. 1999;66(6) p594-601
Objective: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers.
Methods: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled.
Results: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20).
Conclusions: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.
Gear RW, Miaskowski C, Gordon NC, et al
Pain. 1999;83(2) p339-45
Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.
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