Influence of protein‐calorie malnutrition on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats

Varma, Daya R.; Yue, Tian‐Li

doi:10.1111/j.1476-5381.1984.tb10127.x

Cited by 19 publications

(22 citation statements)

References 15 publications

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“…We found that a conventional two-compartment model with a zero-order absorption process best described the pharmacokinetics of DEX in our study. Both onecompartment [33,34] and two-compartment models [35] have been found to best describe DEX plasma concentration profiles [34] . The first-order absorption of DEX has been reported previously [36] .…”

Section: Discussionmentioning

confidence: 99%

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Deng

et al. 2012

Acta Pharmacol Sin

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Aim: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. Methods: A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h posttreatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NON-MEM version 7.1.2. Results: A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg --1 ·h -1 , 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29-and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. Conclusion: A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug-and system-specific PK/PD parameters for the course of induction.

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Section: Discussionmentioning

confidence: 99%

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Deng

et al. 2012

Acta Pharmacol Sin

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“…The pharmacokinetics of dexamethasone has been well studied [4][5][6], however, all the information has been generated after intravenous dosing. This is usually achieved by administering the drug through an externally implanted cannula, tail vein or the penile vein.…”

Section: Introductionmentioning

confidence: 99%

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

Samtani

Jusko

2005

Biopharm & Drug Disp

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This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (IM) route of drug administration vs intravenous (IV) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.

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“…Animals had free access to tap water and a normal Purina rat chow instead of the semi-synthetic diet used in the previous study (Varma & Yue, 1984). Urine glucose was measured daily with glucose labsticks (Billilabstix, Miles Laboratory, Rexdale, Ontario, Canada); 0.1 ml blood was collected between 08 h 30 min-09 h 30 min on day 20 of gestation before the start of the experiments for the determination of blood glucose on a Beckman Autoanalyser according to a glucose oxidase method (Kadish et al, 1968).…”

Section: Methodsmentioning

confidence: 99%

“…Experiments were performed on Sprague-Dawley nonpregnant and pregnant (day 20 of gestation) rats of comparable ages (14-16 weeks old) according to the protocol described in the previous paper (Varma & Yue, 1984); only additional techniques are described below in any detail.…”

Section: Methodsmentioning

confidence: 99%

Influence of streptozotocin‐diabetes on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats

Mulay

Varma

1984

British J Pharmacology

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The influence of streptozotocin‐diabetes on the pharmacokinetics, placental transfer and tissue localization of dexamethasone was determined in Sprague‐Dawley rats. Diabetes significantly increased the volume of distribution of dexamethasone in pregnant but not in nonpregnant rats; plasma half‐life was not significantly increased. Concentrations of maternally administered dexamethasone in all tissues studied (maternal and foetal serum and livers, foetal lungs and placentas) except the amniotic fluid were lower in diabetic than in control animals. Diabetes did not alter the binding of dexamethasone to maternal or foetal serum proteins. Insulin treatment partially reversed the effects of diabetes on the maternal‐foetal exchange of dexamethasone. Diabetes‐induced decrease in the foetal localization of dexamethasone appears to be caused by a decrease in the maternal serum levels as well as by an increase in the foetal excretion of the steroid into the amniotic fluid. In so far as the rat model reflects the human situation, the present data suggest that a standard dose of dexamethasone might not be adequate in promoting foetal lung maturation in diabetic pregnancies.

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Influence of protein‐calorie malnutrition on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats

Cited by 19 publications

References 15 publications

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

Influence of streptozotocin‐diabetes on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats

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