Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models.

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Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. Abstract Text:

Anasuya Hazra,Wojciech Krzyzanski,William J Jusko,

Precursor-dependent indirect response (PDIDR) models may describe the tolerance and rebound phenomenon observed for many pharmacodynamic responses where these characteristics are manifested due to the depletion or accumulation of a physiological precursor or cofactor pool responsible for generating drug effects. The purpose of this report is to extend the concepts and applications of these models and to approximate responses and limiting conditions for very large doses of drugs. Asymptotic analysis was performed for qualitative determination of various parameters, such as maximum response (Rmax) and rebound (RBmax), time to maximum response and rebound (TRmax and TRBmax), and area under the effect and rebound curve (ABEC and ABRC) for large doses. Computer simulations were performed to assess the role of dose for both cases where drugs act either by depleting (Model V) or by blocking (Model VI) the endogenous precursor. Simulations showed that Rmax, RBmax, TRBmax, ABEC and ABRC increase with dose, eventually reaching a plateau when Dose/V is very large compared to the efficacy parameters (SC50 or IC50) of the drug. However, TRmax either increased or decreased with dose depending on various system and drug parameters. The limits for these parameters at large doses qualitatively determined by asymptotic analysis closely approximated the plateaus observed from the simulated curves. At large doses, the drug response could be approximated by a Bateman-like function for both Models V and VI. Qualitative analyses along with simulation studies provide a fundamental basis for understanding the temporal aspects of the PDIDR models especially at large doses to describe the tolerance and rebound phenomenon.

Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. Publishing Authors By Initials

A Hazra,W Krzyzanski,WJ Jusko,

For similar pharmaceutical preparations: prodrugs research abstracts see: pharmaceutical preparations: prodrugs research

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Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of pharmacokinetics and pharmacodynamics

VOLUME: 33

Page Numbers: 683-717

Journal Abbreviation:

ISSN: 1567-567X

DAY: 12

MONTH: 10

YEAR: 2006

Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101096520

Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. Keywords Mesh Terms:

KEYWORDS: Prodrugs

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. Information

Substance Name: Prodrugs

Registry Number: 0

Grant and Affiliation Information for Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models.

AFFILIATION: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 565B Hochstetter Hall, Buffalo, NY 14260, USA.

Country: England

AGENCY: United States NIGMS

GRANT: GM 57980

ACRONYM: GM

MEDLINETA: J Pharmacokinet Pharmacodyn

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