Influence of menstrual cycle and gender on alprazolam pharmacokinetics

Kirkwood, Cynthia K.; Moore, Andrea S.; Hayes, Peggy E.; DeVane, C. Lindsay; Pelonero, Anthony L.

doi:10.1038/clpt.1991.157

Cited by 56 publications

(29 citation statements)

References 7 publications

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“…More importantly, this requirement would have greatly increased the likelihood that women would refuse to participate. Given that alprazolam metabolism has not been shown to vary across the menstrual cycle (Kirkwood et al 1991), andCiraulo et al (1996) reported that alprazolam plasma levels were similar in FHP and FHN females following a single dose of alprazolam, we did not feel that collecting plasma levels in the present study was justified. However, changes in both electrophysiological activity and DSST performance have been shown to be correlated with alprazolam plasma levels (Kaplan et al 1998).…”

Section: Discussionmentioning

confidence: 49%

Increased sensitivity to alprazolam in females with a paternal history of alcoholism

2000

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Section: Discussionmentioning

confidence: 49%

Increased sensitivity to alprazolam in females with a paternal history of alcoholism

2000

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“…Ciraulo et al (1988) found that pharmacokinetic variables for alprazolam in 17 abstinent male alcoholics (mean age 42 years) did not differ from 465 values observed in 12 healthy male controls of mean age 39 years. 5.10 Menstrual Cycle Kirkwood et al (1991) found no significant differences in pharmacokinetic parameters for alprazolam among 8 healthy women (mean age 26 years) when tested in the follicular and luteal phases of the menstrual cycle.…”

Section: Renal Diseasementioning

confidence: 89%

“…In 2 of the studies (Greenblatt et al 1983a;Kirkwood et al 1991) gender had no significant effect on alprazolam t'l>, Vd (in L/kg) or CL (in ml/min/kg). However, Kristjansson and Thorsteinsson (1991) observed significantly higher values of CL in young women as opposed to young men.…”

Section: Gendermentioning

confidence: 95%

Clinical Pharmacokinetics of Alprazolam

Greenblatt

Wright

1993

Clinical Pharmacokinetics

341

108

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Alprazolam is a triazolobenzodiazepine that is extensively prescribed in the Western world for the treatment of anxiety and panic disorders. Its benzodiazepine receptor binding characteristics are qualitatively similar to those of other benzodiazepines. The drug is metabolised primarily by hepatic microsomal oxidation, yielding alpha-hydroxy- and 4-hydroxy-alprazolam as principal initial metabolites. Both have lower intrinsic benzodiazepine receptor affinity than alprazolam and appear in human plasma at less than 10% of the concentrations of the parent drug. Plasma concentrations of the 4-hydroxy metabolite exceed those of the alpha-hydroxy derivative, but urinary recovery of alpha-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro. After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%. Pharmacokinetics are dose-independent and are unchanged during multiple-dose treatment. On average, mean steady-state plasma alprazolam concentrations change by 10 to 12 micrograms/L for each daily dosage change of 1 mg/day. Most studies show that alprazolam pharmacokinetics are not significantly influenced by gender. Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients. Pharmacokinetics of alprazolam are not significantly altered in abstinent alcoholics or patients with panic disorder, and are not influenced by the phase of the menstrual cycle in women. Coadministration of cimetidine, fluoxetine, fluvoxamine or propoxyphene significantly impairs alprazolam clearance. However, alprazolam clearance is not altered by coadministration of propranolol, metronidazole, disulfiram, oral contraceptives or ethanol. Imipramine clearance may be impaired if alprazolam is coadministered. Alprazolam does not alter the pharmacokinetics of digoxin. Although a therapeutic concentration range is not clearly established, some studies indicate that optimal reduction of anxiety associated with panic disorder occurs at steady-state plasma alprazolam concentrations of 20 to 40 micrograms/L. Concentrations higher than this may be needed for suppression of the actual panic attacks. Side effects associated with alprazolam (drowsiness, sedation, etc.) are consistent with its primary benzodiazepine agonist action and increase in frequency with higher steady-state plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…These investigators used the metabolism of midazolam to 1'-hydroxymidazolam as an indicator of cytochrome P4503A activity. Owing to overlapping substrate specificities, confusion exists as to which specific isozymes of the CYP3A subfamily may undertake this reaction, as is the case for Alfentanil no difference clearance [79] Alprazolam no difference clearance [80,81] Dextromethophan no difference clearance (N-demethylation) [75,82] Eletriptan no difference clearance [83] Ethylmorphine no difference N-demethylation [84] Midazolam no difference clearance [85,86] Midazolam increase follicular 1-hydroxylation [87] Omeprazole no difference sulphone formation [88] CYP3A4 b…”

Section: Cytochrome P450 Mediated Biotransforma-tionmentioning

confidence: 99%

The Menstrual Cycle and Drug Metabolism

Mitchell¹,

Smith²,

Waring³

2009

CDM

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Within the field of drug metabolism, when addressing quantitative aspects, an average value is traditionally quoted, commonly the arithmetic mean with perhaps an indication of spread. Better still a range of values may be given, thereby acknowledging that various factors may precipitate differences between individuals. A single subject, however, usually only merits a single value. Nevertheless, events such as an acute illness or concurrent drug therapy serve to alert that this value may change substantially over a relatively short time-period, although any potential effects of naturally occurring phenomena, such as the female menstrual cycle, are often overlooked or disregarded. Are the biochemical and physiological changes that occur during the menstrual cycle able to influence xenobiotic metabolism? Is the idea of a stable and unwavering baseline within a single healthy individual flawed? Is it time to reassess our thinking with regards to such aspects? This brief review explores these issues and examines information available within the literature for evidence of potential influences of menstrual cycle events upon drug metabolism, defined as the actual chemical alteration of the parent molecule into another chemical species.

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Influence of menstrual cycle and gender on alprazolam pharmacokinetics

Cited by 56 publications

References 7 publications

Increased sensitivity to alprazolam in females with a paternal history of alcoholism

Increased sensitivity to alprazolam in females with a paternal history of alcoholism

Clinical Pharmacokinetics of Alprazolam

The Menstrual Cycle and Drug Metabolism

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