Assessment of Doxylamine Influence on Mixed Function Oxidase Activity upon Multiple Dose Oral Administration to Normal Volunteers

Thompson, Gary A.; Peter, John; Heise, Mark; Horowitz, Zebulun D.; Salyers, Georgiana C.; Charles, Terri T.; Brezovic, Chris; Russell, D. A.; Skare, Julie A.; Powell, James H.

doi:10.1021/js950443e

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…CL o was reduced in older men compared to younger men with no age effects in women. Upon multiple dosing of 12.5 mg every 6 hours, steady state was achieved within 1 week . Estimated pharmacokinetic parameters included Cl o and CL r of 150 and 110 mL/h/kg, respectively, and a t 1/2,z of ∼14 hours.…”

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confidence: 99%

Doxylamine pharmacokinetics following single dose oral administration in children ages 2–17 years

Balan

Thompson²,

Gibb

et al. 2013

The Journal of Clinical Pharma

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To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

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confidence: 99%

Doxylamine pharmacokinetics following single dose oral administration in children ages 2–17 years

Balan

Thompson²,

Gibb

et al. 2013

The Journal of Clinical Pharma

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“… a Taken from Scavone et al (1989 [140], 1997 [141]) and Thompson et al [142]; b taken from Rumble et al [143]; c taken from Birkett and Miners [144]; d taken from Brogard et al [145]; e taken from Larson et al [146]; f taken from Stuck et al [147]; g taken from Setchell et al [148]; h taken from Hughes, Ilett and Jellett [149] and Verme et al [150]; and i taken from Bres and Bressolle [140]. …”

Section: S1 Model Validation: Prediction Of Norfloxacin Temporal Bramentioning

confidence: 99%

Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

2014

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Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.

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Urinary 6?-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals

Galteau

Shamsa

2003

European Journal of Clinical Pharmacology

144

116

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6beta-Hydroxycortisol (6beta-OHF) urinary excretion has, for a long time, been considered a marker of drug induction and, more recently, of drug inhibition in humans and in laboratory animals, but its specificity is still under debate. In this work, we review 277 papers devoted to 6beta-OHF urinary excretion. We have evaluated factors that could modify 6beta-OHF excretion and, thus, could explain contradictory results. We have examined the effect of the analytical techniques on physiological values. Intra- and inter-individual variability and the effect of circadian rhythms on urinary excretion of 6beta-OHF as well as cortisol and 17-hydroxycorticosteroids have been evaluated. We also give an overview of drugs that induce, inhibit or have no effect on 6beta-OHF. For inducing and inhibiting drugs, we calculated the ranges of variation of 6beta-OHF excretion from the results indicated in the different papers. This work was done for well-known inducers, such as anticonvulsants, but also for other inducing or inhibiting drugs found in the literature. The time-course of variation in 6beta-OHF excretion when different drugs are co-administered was also investigated. The potential relationship between cytochrome P(450) 3A4 (CYP3A4) polymorphism and 6beta-OHF excretion was studied. Finally, the interest of 6beta-OHF urinary excretion was compared with that of other tests proposed to measure CYP3A4 activity. This review demonstrates that 6beta-OHF urinary excretion is a good test to evaluate drug-metabolising enzyme inducing or inhibiting properties of drugs when the subjects are their own controls, but this test is not reliable enough to measure actual CYP3A4 activity.

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Assessment of Doxylamine Influence on Mixed Function Oxidase Activity upon Multiple Dose Oral Administration to Normal Volunteers

Cited by 3 publications

References 52 publications

Doxylamine pharmacokinetics following single dose oral administration in children ages 2–17 years

Doxylamine pharmacokinetics following single dose oral administration in children ages 2–17 years

Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

Urinary 6?-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals

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