Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity.
Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vss per kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.
Dunn
T E
TE
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Ludwig
E A
EA
Slaughter
R L
RL
Camara
D S
DS
Jusko
W J
WJ
D000328:Adult; D001491:Basophils / Q000378:metabolism; D002940:Circadian Rhythm; D004341:Drug Evaluation; D006632:Histamine / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D008775:Methylprednisolone / Q000493:pharmacokinetics*; D008776:Methylprednisolone Hemisuccinate / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009765:Obesity / Q000378:metabolism*; D012044:Regression Analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects
D008776:Methylprednisolone Hemisuccinate; D006632:Histamine; D006854:Hydrocortisone; D008775:Methylprednisolone