CORTICOSTEROID PHARMACOKINETICS AND PHARMACODYNAMICS

State University Of New York At Buffalo, Buffalo NY

Investigators

Linked publications & trials

Abstract

major factors determining corticosteroid receptor binding and pharmacodynamics will be measured and improved mathematical models for quantitating the pharmacokinetics and pharmacodynamics (PK/PD) of corticosteroids will be sought. These important drugs exert many of their hormonal, immunosuppressive, and anti-inflammatory effects by diffusion into cells, reversible binding to cytosolic receptors, and then either have direct effects on biochemical processes or produce gene/mRNA-mediated synthesis or inhibition of diverse effector proteins or enzymes. The major hypothesis is that realistic and comprehensive PK/PD models of corticosteroid action are feasible which permit more mechanistic insights into drug, dosage, and interaction factors which determine corticosteroid effects. One specific aim is to extend our current gene-mediated models of steroid PK/PD in rats (measuring steroid disposition, hepatic receptors and MRNA, and hepatic TAT mRNA and TAT enzyme) to account for receptor MRNA down regulation and multiple-dose effects. The second specific aim is to extend our current models of corticosteroid immunosuppression (ex vivo cell proliferation, splenocyte receptor binding, and cell trafficking) to assess PK/PD interactions with important agents which may alter or synergize corticosteroid immunosuppression. These include estradiol, DHEA (dehydroepiandrosterone), Interleukin-10, and sirolimus (rapamycin). These studies will improve the implementation of corticosteroid therapy alone and in combination as well as continue the generation of an important class of pharmacodynamic models which apply to drugs causing effects by complex and indirect mechanisms.