Mathematical modeling of biodistribution of an antisense oligodeoxynucleotide phosphorothioate (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Mathematical modeling of biodistribution of an antisense oligodeoxynucleotide phosphorothioate (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A2166 1995. Unique Identifier : AIDSLINE ICDB/95609941
Liu T; Lu Z; Diasio RB; Agrawal S; Zhang R; Univ. of Alabama, Birmingham, AL 35294

Abstract: A 25-mer antisense oligodeoxynucleotide phosphorothioate (PS-oligonucleotide) has been demonstrated to have anti-HIV activity in various assay models. Pharmacokinetics and biodistribution of this PS-oligonucleotide have recently been determined in rats by iv bolus administration of 35S-labeled PS-oligonucleotide (Zhang et al, Biochem Pharm, in press). In the present study, a mathematical model is developed for biodistribution of this PS-oligonucleotide. Based on the time serial concentration data, correlation and regression analyses were first carried out to determine the relationships between plasma concentration and tissue concentrations. Linear relationships between plasma and most tissue concentrations were found except for the kidney. By using a computer program (ADAPT), input and output rate constants for each tissue were estimated. We began the modeling with 15 selected tissues and 34 rate constants and selected a final model based on Akaikie's Information Criterion and standard errors of estimated rate constants. To improve the goodness of fit of the model, nonlinear components of Michaelis-Menten model were included for kidney and liver disposition. Satisfactory agreement was achieved between predicted and measured values, permitting an accurate evaluation of the kinetics and tissue disposition of the PS-oligonucleotide. Using the above methods, comparative mathematical modeling for pharmacokinetics of several other antisense oligonucleotides is being performed.

Keywords: Antiviral Agents/*PHARMACOKINETICS *Computer Simulation Human HIV/DRUG EFFECTS *Models, Statistical Oligonucleotides, Antisense/*PHARMACOKINETICS Tissue Distribution ABSTRACT
951230
M95C3235

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