Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects.
Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylprednisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.
Kong
A N
AN
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Ludwig
E A
EA
Slaughter
R L
RL
DiStefano
P M
PM
DeMasi
J
J
Middleton
E
E
Jusko
W J
WJ
D000328:Adult; D000704:Analysis of Variance; D001491:Basophils / Q000032:analysis / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D006632:Histamine / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D016018:Least-Squares Analysis; D008297:Male; D008775:Methylprednisolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008776:Methylprednisolone Hemisuccinate / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D011485:Protein Binding; D011863:Radioimmunoassay
D001798:Blood Proteins; D008776:Methylprednisolone Hemisuccinate; D006632:Histamine; D006854:Hydrocortisone; D008775:Methylprednisolone