Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Abstract

Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T-helper, T-suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight-normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by22%in whites and40%in blacks for oral clearance, p < 0.01; by32%in whites and38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC 50 ) values for T-suppressor cell-trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC 50 or SC 50 values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings.The role of sex as a factor in the pharmacokinetics and the pharmacodynamics (PK/PD) of drugs has become well appreciated. 1 Women often exhibit modestly more rapid clearances of drugs metabolized by the CYP3A4 pathway (e.g., methylprednisolone 2 ). They may also show alterations in the disposition of drugs in relation to the phase of the menstrual cycle (e.g., theophylline 3 ), pregnancy (e.g., caffeine 4 ), or after menopause (e.g., verapamil 5 ). Women receiving oral contraceptives are likely to show more rapid clearances of conjugated NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript drugs (e.g., oxazepam) but have reduced clearances of many oxidized compounds (e.g., prednisolone 6 ). Interpretation of data is sometimes complicated by the need to assess whether pharmacokinetic parameters are properly normalized for body weight differences and if the phase of the menstrual cycle was monitored.The assessment of pharmacodynamic differences between men and women requires control of pharmacokinetic factors and use of appropriate methodology to relate responses to plasma or biophase drug concentrations. There are some notable examples of marked sex differences in drug efficacy. As...

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