Age‐ and Gender‐Related Differences in Diazepam Pharmacokinetics

MacLeod, Stuart; Giles, H. G.; Bengert, B.; Liu, F. F.; Sellers, Edward M.

doi:10.1002/j.1552-4604.1979.tb01612.x

Cited by 88 publications

(29 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19,20 Such differences might lead to higher blood levels of mefloquine in women and thus explain their higher rate of side effects. One may also hypothesize that, because of a relatively lower body weight, women may have higher blood levels of mefloquine and thus more adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Serious adverse events of mefloquine in relation to blood level and gender.

Schwartz¹,

Potasman²,

Rotenberg³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Mefloquine is widely used for prophylaxis in areas with chloroquine-resistant falciparum malaria. As the use of mefloquine has increased, so have the reports on its adverse effects. We sought to evaluate the possible association between serum levels of mefloquine and serious side effects caused by this drug by means of a casecontrol design study. The study population included 17 patients who presented to emergency rooms or travel clinics with symptoms suggesting serious adverse effects of mefloquine and 28 controls (healthy people, still taking mefloquine after travel). The mean age of the patients and the controls was 31.5 Ϯ 11.6 years and 34 Ϯ 12.2 years, respectively. The percentage of women among the patients was higher than in the control population (76% versus 40%, respectively; P ϭ 0.03). Most of the complaints were related to the central nervous system (13 of 17); 5 patients interrupted their trip and 2 others were hospitalized. No difference in the level of mefloquine in the blood was found between the patients and the control groups. Also, no significant difference was found between mefloquine levels in the blood of men and women. These results suggest that blood levels of mefloquine do not correlate with its severe adverse events. Women tended to be more susceptible than men, despite having similar blood levels of the drug.

show abstract

Section: Discussionmentioning

confidence: 99%

Serious adverse events of mefloquine in relation to blood level and gender.

Schwartz¹,

Potasman²,

Rotenberg³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

show abstract

“…The higher bioavailability of aspirin in women than in men has been linked to decreased conjugation with glycine and glucuronic acid (Franconi et al, 2007). Men show a higher rate of clearance of the benzodiazepines diazepam, chlordiazepoxide, and olanzapine (MacLeod et al, 1979;Roberts et al, 1979;Bigos et al, 2008). Likewise, women display greater sensitivity to diazepam, which can lead to impairment of psychomotor skills (Palva, 1985).…”

Section: Sex Differences In Hepatic Drug Metabolismmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

634

584

View full text Add to dashboard Cite

Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

show abstract

“…The most important findings to emerge have been (i) a reduction in the rate of biotransformation of oxidatively metabolised compounds (especially in males) corresponding to that observed with antipyrine (Greenblatt et *Present address and correspondence: Department of Geriatric Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN al., 1982), (ii) an increase in the distribution volume of these compounds (Klotz et al, 1975;Shader et al, 1977;MacLeod et al, 1979;Allen et al, 1980;Greenblatt et al, 1981) and (iii) absence of any major effect of age on the rate of elimination of those drugs metabolised via nonoxidative routes, such as conjugation .…”

Section: Introductionmentioning

confidence: 99%

Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations.

Swift¹,

Ewen²,

Clarke³

et al. 1985

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The immediate and residual response to single doses of oral diazepam 10 mg was measured in 11 young and 12 elderly healthy volunteers using postural sway, digit symbol substitution scores and subjective ratings. 2 The effect on postural sway was markedly accentuated in the older volunteers, but the difference between groups in the effect on the other measures used did not achieve significance. 3 The corresponding plasma total diazepam concentrations were lower in the older subjects beyond 0.5 h post dose and the concentrations of plasma desmethyldiazepam did not differ between the groups. 4 Diazepam plasma protein binding was significantly reduced in the elderly subjects, but the plasma free (unbound) diazepam concentrations did not exceed those in the young group. 5 There was poor correlation between the responses measured and the concentrations of either total diazepam, desmethyldiazepam or free diazepam. 6 The results suggest the occurrence of a non-uniform effect of age on different aspects of benzodiazepine response, and that where an accentuated effect occurs the mechanisms are substantially pharmacodynamic.

show abstract

Age‐ and Gender‐Related Differences in Diazepam Pharmacokinetics

Cited by 88 publications

References 12 publications

Serious adverse events of mefloquine in relation to blood level and gender.

Serious adverse events of mefloquine in relation to blood level and gender.

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations.

Contact Info

Product

Resources

About