Gender Differences in P-Glycoprotein Expression and Function: Effects on Drug Disposition and Outcome

Bebawy, Mary; Chetty, Manoranjenni

doi:10.2174/138920009788498996

Cited by 64 publications

(53 citation statements)

References 84 publications

(123 reference statements)

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“…Although gender differences in intestinal P-glycoprotein activity are not evident [13,14], hepatic activity of this enzyme is reported to be lower in women than in men [10,12,13], which could result in less biliary excretion of ticagrelor/AR-C124910XX, leading to increased blood levels. Furthermore, potential differences in renal P-glycoprotein are not considered to have played a role in age-and gender-related changes in ticagrelor PK parameters.…”

Section: Discussionmentioning

confidence: 98%

“…For example, age-and gender-related physiological differences (e.g., gastrointestinal motility, body composition, liver mass, and renal function) can affect drug disposition [9,10]. The activity of P-glycoprotein, a key drug-transporter protein [11], is lower in the liver of women than in men [12] and comparable between genders in the intestine [13,14]. The influence of age on P-glycoprotein activity has not been characterized [15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

Teng

Mitchell

Butler

2012

Eur J Clin Pharmacol

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Purpose The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD). Methods Forty healthy individuals [18-45 years (young); ≥65 years (elderly); ten men, ten women per age group) received 200 mg ticagrelor. Results Ticagrelor was rapidly absorbed [time to maximum concentration (C max ) (t max ) 2.5-3.0 h], and its major active metabolite, AR-C124910XX rapidly formed (t max 3.0-3.5 h) in all groups. Ticagrelor exposure was higher in elderly vs. the young [area under the curve from time 0 to infinity (AUC 0-∞ ) 52%; C max 63% higher] and women vs. men (AUC 0-∞ 37%; C max 52% higher). Mean terminal elimination half-life was slightly longer in women vs. men but was unaffected by age. Similar results were observed for AR-C124910XX (elderly vs. young, AUC 0-∞ 48%; C max 61% higher), and in women vs. men (AUC 0-∞ 55%; C max 56% higher). Across all groups, ticagrelor produced substantial final-extent inhibition of platelet aggregation (IPA): >90% at 4 and 8 h postdose. Individuals with highest ticagrelor exposure (i.e., elderly) had the lowest IPA, indicating an age-related platelet sensitivity effect. In young individuals, platelet sensitivity was greater in men vs. women. Ticagrelor tolerability was not affected by age or gender. Conclusions Systemic exposures to ticagrelor and AR-C124910XX were higher in elderly vs. young and in women vs. men. Age-and gender-related changes in IPA were apparent, but substantial IPA was achieved in all groups.No adjustment in ticagrelor dose should be considered necessary based on age and gender.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

Teng

Mitchell

Butler

2012

Eur J Clin Pharmacol

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“…It has been hypothesized that sex-related differences in the clearance of CYP3A4 substrates may be caused by P-glycoprotein [22]. P-glycoprotein may contribute to a higher exposure in female subjects as a result of lower enterocyte P-glycoprotein content in women [23]. Other results did not confirm this observation, and no sex differences in P-glycoprotein in humans were found using fexofenadine as a probe substrate [24].…”

Section: Discussionmentioning

confidence: 99%

Single-Dose Pharmacokinetics of the Renin Inhibitor ACT-077825 in Elderly and Young Subjects of Both Sexes

2014

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Background/Aims: The study objective was to investigate and compare the pharmacokinetics of a single oral dose of ACT-077825, a novel direct renin inhibitor, in young and elderly, male and female healthy subjects and to evaluate the safety and tolerability of ACT-077825 in these population groups. Methods: A total of 32 healthy subjects were included in this single-center, open-label study. The subjects were divided into 4 groups, including 8 young male, 8 young female, 8 elderly male and 8 elderly female subjects. Each participant received a single 200-mg dose of ACT-077825. Blood samples were taken over 5 days (120 h) to determine the plasma levels of ACT-077825. Safety and tolerability were monitored using standard assessments before drug administration, on the administration day and at the end of the blood sampling period. Results: Upon pooling male and female subjects, exposure was higher in elderly compared to young subjects, showing an increase of 65% for AUC_0-_∞, 40% for C_max and 38% for t_1/2. While young male and female subjects showed similar plasma profiles and exposure, a significant increase in exposure occurred with age in both sexes compared to younger subjects. The difference was largest between young and elderly females. Furthermore, the exposure to ACT-077825 was around 30% higher in elderly female compared to elderly male subjects. ACT-077825 was well tolerated by all groups, including the elderly females who showed the highest exposure. Conclusions: ACT-077825 exposure is moderately increased in elderly subjects. The clinical relevance of this observation should be explored in the context of further studies.

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“…The primary reason for the use of male rats in the latter studies is our emerging interest on the impact of SCI on the blood-testis barrier, 77 causing our laboratory to switch to the use of male rats during the course of this study. Although previous studies have indicated that there are gender-associated differences in Pgp transport activity in body tissues of experimental animals and humans, 110 we have not yet investigated whether there is a differential impact of SCI on Pgp expression and/or function in male and female rats. We have compared baseline Pgp expression in uninjured male and female rats, as well as at 72 h after SCI, and we have detected no gender-associated differences (data not shown).…”

Section: Increased P-glycoprotein Expression and Activity In The Injumentioning

confidence: 94%

The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord

Dulin¹,

Moore²,

Grill³

2013

Journal of Neurotrauma

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There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male SpragueDawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord.

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Gender Differences in P-Glycoprotein Expression and Function: Effects on Drug Disposition and Outcome

Cited by 64 publications

References 84 publications

Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

Single-Dose Pharmacokinetics of the Renin Inhibitor ACT-077825 in Elderly and Young Subjects of Both Sexes

The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord

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