Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects

Kong, Ah Ng Tony; Ludwig, Elizabeth; Slaughter, Richard L.; DiStefano, Providence M.; DeMasi, James; Middleton, Elliott; Jusko, William J.

doi:10.1038/clpt.1989.196

Cited by 74 publications

(58 citation statements)

References 45 publications

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“…Recently pharmacodynamic models that describe the direct suppressive effects of corticosteroids have been used to characterize the response patterns of plasma cortisol concentrations, blood basophil counts (measured as whole blood histamine), and helper T lymphocyte counts after administration of methylprednisolone to young healthy male subjects. [15][16][17] These models are applied in this study to jointly examine the pharmacokinetics and pharmacodynamics of methylprednisolone in relation to gender. …”

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Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Lew

Ludwig

Milad

et al. 1993

Clin Pharmacol Ther

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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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Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics

Lew

Ludwig

Milad

et al. 1993

Clin Pharmacol Ther

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155

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“…Several studies have shown that 10 to 40 mg methylprednisolone administered in the morning produce appreciable suppression of cortisol concentrations. 19,36,37 We found a similar degree of net suppression of cortisol concentrations in both phases; however, the normal circadian rhythm was significantly altered by the 4 PM dose. This dose produces nadir cortisol concentrations around the time that cortisol concentrations are normally increasing, thus perturbing the normal circadian cycle.…”

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confidence: 99%

“…Pharmacodynamic models that describe these direct suppressive effects are shown with the experimental data. 19,30 These models account for both the pharmacokinetics of the administered corticosteroid along with the suppression and return to baseline of the measured pharmacodynamic parameter.After intravenous administration of methylprednisolone, whole blood histamine (H) concentrations decline linearly with a first-order rate constant (k h ). Corticosteroids arc postulated to inhibit the zero-order rate of return of basophils from the extra vascular compartment to the blood , whereas the movement of basophils from the blood is unaffected.…”

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“…Pharmacodynamic models developed in this laboratory for these effects were used. 19,20 Methylprednisolone, rather than prednisolone, was chosen for study because its kinetics is linear at low doses and thus less complicated to study. 21 …”

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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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Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on‐line solid‐phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva

Ruiter

Teeninga

Nauta

et al. 2011

Biomedical Chromatography

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Prednisolone (PLN) and prednisone (PN) are widely used glucocorticoids. Drug monitoring of PLN and PN is not routinely done owing to the need for multiple blood sampling and challenging measurement of unbound PLN and PN in blood. Here we present a robust method for quantification of cortisol, PLN and PN in serum, ultrafiltrate and saliva by on-line solid-phase extraction LC-MS/MS. The method is linear for the three analytes over the range of 6-1400 nmol/L for serum and 2-450 nmol/L for ultrafiltrate and saliva. Within-run precision of all three analytes was <10% and total precision was <15%. This method was applied to create time-concentration profiles of cortisol, PLN and PN after an oral dose of prednisolone in a healthy volunteer. Salivary levels of PLN correlated well with ultrafiltrate levels (p < 0.01), while this correlation was only marginal for PN (p = 0.052). The PN/PLN ratio was significantly higher in saliva than in ultrafiltrate and serum (p < 0.01). Addition sums of both metabolites in saliva showed excellent correlation with those of ultrafiltrate (p < 0.01). These findings have not been presented before and may have important implications for future studies concerning drug monitoring of PLN and PN in saliva.

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Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects

Cited by 74 publications

References 45 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

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on‐line solid‐phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva

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