Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics.
A two-compartment closed model was used to characterize the movement of basophils between blood and extravascular sites resulting from methylprednisolone (MP) exposure. This model is consistent with the view that corticosteroids cause a decrease in the recirculation of these cells from peripheral compartments. Methylprednisolone (Solu-Medrol) was given to healthy males at doses of 10, 25, and 40 mg. Blood samples were collected and assayed for MP by HPLC for pharmacokinetic analysis. Whole blood histamine, an index of circulating basophils, was assessed by RIA over 32 hr. Nonlinear least-squares analysis was carried out to solve for the model parameters reflecting cell movement between compartments and sensitivity (IC50) to the steroid. This model quantitiates the fall and return pattern of biologic response to corticosteroids with a minimal number of parameters which jointly fit several dose/response curves and yields a mean IC50 value of 8.1 ng/ml similar to receptor binding of MP. Properties of the temporal and integrated response curve and model extrapolations over a wide dose range were explored with simulations. Because corticosteroids exert similar effects on other cells in blood, this model may be applicable to various regulatory and immunosuppressive effects.
Wald
J A
JA
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Salazar
D E
DE
Chen
H Y
HY
Jusko
W J
WJ
D000305:Adrenal Cortex Hormones / Q000493:pharmacokinetics / Q000494:pharmacology; D001491:Basophils / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000097:blood; D006801:Humans; D008297:Male; D008432:Mathematical Computing; D008775:Methylprednisolone / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological
D000305:Adrenal Cortex Hormones; D006632:Histamine; D008775:Methylprednisolone