Alterations in prednisolone disposition as a result of time of administration, gender and dose.

Meffin, Peter J.; Brooks, P. M.; Sallustio, Benedetta C.

doi:10.1111/j.1365-2125.1984.tb02363.x

Cited by 56 publications

(42 citation statements)

References 28 publications

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“…The remaining blood was centrifuged and the plasma harvested and frozen at −20° C until assayed. In addition, 4 ml blood was drawn into EDTA tubes at 0, 2,4,8,12,16,20, and 24 hours for the determination of helper T lymphocyte counts.During the methylprednisolone phase, each subject received an intravenous bolus dose of methylprednisolone sodium succinate (Solu-Medrol; The Upjohn Company, Kalamazoo, Mich.) into the arm contralateral to the one used for blood sampling. A dose of 0.6 mg/kg ideal body weight (IBW) methylprednisolone was used to provide a similar initial blood concentration of methylprednisolone in each subject (as attained in a typical 70 kg man after a 40 mg dose) and to ensure a detectable suppressive response.…”

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confidence: 99%

“…As early as 1958, a gender-related difference in hepatic metabolism of corticosteroids had been noted in rats by Yates et al 10 In humans, two studies have found a 23% and 21% greater clearance of free prednisolone in female compared with male adult subjects. 11,12 Gender-related differences may also influence the pharmacodynamics of drugs, but this has not been studied extensively. An in vitro study evaluating whole blood platelet aggregation revealed that the antithrombotic effect of aspirin was significantly greater in men, most likely because of the difference in testosterone levels.…”

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confidence: 99%

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Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Lew

Ludwig

Milad

et al. 1993

Clin Pharmacol Ther

155

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The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half-life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC 50 ) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration-time curve of effect was similar for both groups. The IC 50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 24-hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response.Male subjects typically have been used in most drug studies. However, the findings of these studies are applied clinically to both male and female patients, despite their physiologic differences. Of the studies that have enrolled both men and women, most fail to analyze their findings by gender and instead treat all the subjects as one homogeneous group. 1 This bias in clinical research has been of concern within the health professions. [2][3][4] The literature currently lacks guidelines regarding dosing regimens based on gender.Copyright © 1993 by Mosby-Year Book, Inc.Reprint requests: William J. Jusko, PhD, Hochstetter 565, School of Pharmacy, State University or New York at Buffalo, Buffalo, NY 14260. Presented at the Ninety-fourth Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 24-26, 1993, Honolulu, Hawaii (Abstract: Clin Pharmacol Ther 1993;53:183). NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2014 October 23. Published in final edited form as:Clin Pharmacol Ther. 1993 October ; 54(4): 402-414. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGender-related differences in disposition have been observed for numerous drugs. The total and unbound clearance of diazepam, which undergoes oxidative metabolism, was found to be greater in women. 5 Clearance of oxazepam (total and unbound) 6 and acetaminophen, 7 both of which undergo glucuronide conjugation, is significantly greater ...

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confidence: 99%

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confidence: 99%

Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Lew

Ludwig

Milad

et al. 1993

Clin Pharmacol Ther

155

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“…Both theophylline and free prednisolone, which are metabolized by the mixed function oxidase system, were found to exhibit lower CL values after morning administration than after afternoon administration, with CL values differing by 14% to 22%. 8,9,28 No such differences were found in the metabolic CL of acetaminophen, but this drug is primarily cleared by way of conjugation as opposed to oxidation. 29 In our study, the mean CL of methylprednisolone, which is eliminated by the mixed function oxidase system, was lower in the morning than in the afternoon, resulting in a larger AUC after the 8 AM dose.…”

Section: Discussionmentioning

confidence: 99%

“…The second study 8 found circadian differences in the clearance (CL) of free prednisolone and the free fraction when it was given as a low dose. The third study 9 found circadian variation in all parameters investigated. To date, no human chronopharmacokinetic study with methylprednisolone has been reported.…”

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confidence: 85%

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

Fisher

Ludwig

Wald

et al. 1992

Clin Pharmacol Ther

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The temporal variations in the pharmacokinetics and pharmacodynamics of methylprednisolone at 8 AM versus 4 PM were investigated in six healthy male volunteers. Subjects completed three phases: no drug administration, 20 mg intravenous methylprednisolone at 8 AM, and the same dose at 4 PM. Methylprednisolone clearance was 28% greater in the afternoon. The suppressive effects of methylprednisolone on basophils (measured as whole blood histamine), helper T lymphocytes, and cortisol concentrations, assessed by the ratio of the area under the curve (AUC) after methylprednisolone to the baseline AUC, were not different between the phases. The 50% inhibitory concentration values for methylprednisolone derived from pharmacodynamic models were also similar, indicating no difference in intrinsic responsiveness. However, cortisol concentrations returned to baseline about 4 hours earlier after the 4 PM compared with the 8 AM dose because of the enhanced afternoon methylprednisolonc clearance. These findings are in agreement with other studies that suggest adequate clinical effects and less disturbance of cortisol circadian behavior when methylprednisolone is administered as a single dose in the morning.Corticosteroids are an important class of therapeutic agents because of their antiinflammatory and immuno-suppressive properties. Ideal dosing regimens have yet to be elucidated for the treatment of numerous disease states. Currently, corticosteroids are most often administered as a single morning dose. However, these agents may be administered as divided doses or even as a single evening dose in those conditions requiring adrenal suppression. 1 Numerous drugs, including theophylline, 2 phenyloin, 3 and cisplatin, 4 have demonstrated temporal variations in their pharmacokinetics. This is not surprising because it has been shown in animals that both hepatic drug-metabolizing activities and renal clearance (CL R ) mechanisms exhibit circadian variations. 5,6 Human chronopharmacokinetic studies with exogenous corticosteroids are limited. Prednisolone has been evaluated in three studies with conflicting findings. The first study 7 found no circadian differences in prednisolone Copyright © 1992 clearance, volume of distribution (V), or half-life (t ½ ). The second study 8 found circadian differences in the clearance (CL) of free prednisolone and the free fraction when it was given as a low dose. The third study 9 found circadian variation in all parameters investigated. To date, no human chronopharmacokinetic study with methylprednisolone has been reported. In male Norwegian rats, the maximum methylprednisolone t ½ was noted to occur when the drug was administered at 6 PM, the commencement of the nocturnal activity period of the animals, whereas the shortest t ½ was documented with noon administration, or midway through the diurnal rest span. 10 The pharmacodynamics of exogenous corticosteroids may show temporal variations. The susceptibility of the hypothalamic-pituitary-adrenal axis to suppression in humans, as measured...

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“…Approximately 2%-5% is excreted in the urine as prednisone. [44] The clearance of prednisolone is dose-dependent, [31][32][33], [44], [59], [60,64] due to the concentration-dependent protein binding, that is, at high doses the increased free fraction of prednisolone is reflected in a greater plasma clearance and apparent volume of distribution. The total body clearance of prednisolone has been reported to be 111 mL/min/1.73 m2 for a 5 mg dose and 194 mL/min/1.73 m2 for a 40 mg dose of prednisolone.…”

Section: Metabolism and Excretionmentioning

confidence: 99%

Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Prednisolone

Vogt

Derendorf

Krämer³

et al. 2007

Journal of Pharmaceutical Sciences

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A project of the International Pharmaceutical Federation FIP, Groupe BCS, www.fip.org. This article reflects the scientific opinion of the authors and not the policies of regulating agencies. AbstractLiterature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

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Alterations in prednisolone disposition as a result of time of administration, gender and dose.

Cited by 56 publications

References 28 publications

Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Prednisolone

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