The Influence of Age and Sex on the Clearance of Cytochrome P450 3A Substrates

Cotreau, Monette M.; Moltke, Lisa L. von; Greenblatt, David J.

doi:10.2165/00003088-200544010-00002

Cited by 266 publications

(202 citation statements)

References 170 publications

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“…1), which is consistent with previous studies using CYP3A substrates or markers (Horsmans et al, 1992;Harris et al, 1995;Inagaki et al, 2002;Zhu et al, 2003;Cotreau et al, 2005;Lutz et al, 2010); however, we found no statistically significant sex-related difference (P = 0.37). The presence of the female sex steroids estrogen and progesterone in vivo may play a role in the modulation of this sex-related difference.…”

Section: Discussionsupporting

confidence: 92%

Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

et al. 2012

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This study was designed to evaluate the in vivo activity of cytochrome P450 3A (CYP3A) in 49 healthy Japanese subjects aged 22-58 years using endogenous cortisol 6b-hydroxylation clearance [CLm(6b)], a novel biomarker for CYP3A phenotyping. CLm(6b) in the 49 healthy subjects was 2.40 6 0.79 ml/min with an approximately 4-fold interindividual variability of CYP3A activity. The mean clearance in the 24 women was 2.50 6 0.89 ml/min; the value in the women was higher than in the 25 men (2.30 6 0.69 ml/min) by approximately 9%. We also measured the change of CLm(6b) in 14 healthy subjects in the morning at 10:00-12:00 every 2 or 3 days over a period of 36-53 days and observed a 1.5-fold to 3.4-fold dayto-day intraindividual variability in the CYP3A activity. The mean value for CLm(6b) in each subject for 36-53 days was 2.54 6 0.76 ml/min (n = 14). We also evaluated the CLm(6b) every 2 hours from 8:00-20:00 in 26 healthy subjects. The within-day intraindividual clearance variability was 1.1-fold to 2.5-fold (2.45 6 0.91 ml/min, n = 26). No characteristic diurnal rhythms were observed in the in vivo activity of CYP3A.

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Section: Discussionsupporting

confidence: 92%

Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

et al. 2012

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“…45 In men aged X65 years, the AUC of sildenafil was about twice as high and mean C max values about 60-70% higher than in younger men. 34,35 For vardenafil, the AUC and C max are increased by 52 and 34%, respectively, in elderly men.…”

Section: Pde5 Inhibitors In Special Populationsmentioning

confidence: 86%

The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy

et al. 2006

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Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) relationships and their relevance to dose selection and applied pharmacotherapy. It is followed by a detailed comparative discussion on the pharmacokinetics and exposure-response relationship of the currently available PDE5 inhibitors, including known drug-drug interactions and dosage adjustments in special populations. The review is aimed at providing a critical assessment of the pharmacokinetics of PDE5 inhibitors, which may assist clinicians in tailoring drug and/or treatment regimens to the unique needs of each individual patient with erectile dysfunction.

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“…MDZ is rapidly and extensively metabolized by the liver and intestinal microsomal enzymes (Heizmann and Ziegler, 1981;Kronbach et al, 1989). Many factors, such as age and sex (Hunt et al, 1992;Gibbs and Hosea, 2003;Wojnowski, 2004;Cotreau et al, 2005), concomitant medication (von Moltke et al, 1996), and hepatic function (Gibbs and Hosea, 2003), may influence the activity of CYP3A isoforms.…”

Section: Introductionmentioning

confidence: 99%

Effect of hepatic function on the EC50 of midazolam and the BIS50 at the time of loss of consciousness

Ruan

2014

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To explore the effect of hepatic function on loss of consciousness (LOC) and bispectral index (BIS) during sedation with midazolam (MDZ). Methods: Forty-five patients were assigned to three groups according to their liver function. Thirty of these patients with diagnoses of cholelithiasis were scheduled laparoscopic cholecystectomy, including 15 patients with normal liver function (normal group), and 15 patients with moderately abnormal liver function based on the results of ultrasonic diagnosis of a moderately fatty liver and elevated alanine transaminase levels of less than three times normal (moderate group). The other 15 patients with end-stage liver disease (severe group) underwent liver transplantation. Each patient was administered MDZ by way of target-controlled infusion to increase the concentration gradually. At the time of LOC, the BIS was recorded and a blood sample was withdrawn for measurement of the concentration of MDZ. The concentration of MDZ (EC 50 ) and the BIS value (BIS 50 ) at which 50% of patients lose consciousness were calculated using logistic regression. Results: At the time of LOC, the EC 50 of MDZ and the BIS 50 were similar in the normal and moderate groups (P>0.05). LOC occurred at a lower EC 50 of MDZ and at a higher BIS 50 in the severe group, compared with the normal and moderate groups (P<0.01). Conclusions: Patients with end-stage liver disease were more sensitive to MDZ and this affected the prediction of their time of LOC following MDZ administration. There were no changes in response in patients with moderately abnormal hepatic function.

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The Influence of Age and Sex on the Clearance of Cytochrome P450 3A Substrates

Cited by 266 publications

References 170 publications

Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy

Effect of hepatic function on the EC50 of midazolam and the BIS50 at the time of loss of consciousness

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