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dc.contributor.authorAbu-Raddad, Eyas Jamal
dc.description.abstractThe pharmacokinetics of a hypothetical prodrug of a cytosine analogue, and the stereoselective and allometric scaling of the pharmacokinetics of a cytidine analogue are investigated. Flucytosine (5-fluorocytosine, 5-FC) has been used for decades to treat systemic fungal infections, but its use was limited by serious side effects at high plasma concentrations. The azido-pyrimidine, 4-azido-5-fluoro-2(1H)-pyrimidinone (A-5-FP) has been synthesized as a potential prodrug for 5-FC in an attempt to dampen high concentrations encountered with 5-FC administration. 2',3'-Dideoxy-5-fluoro-3'- thiacytidine (RCV; Racivir™), is a chiral compound whose enantiomers are potent inhibitors of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). A-5-FP did not convert to 5-FC after intravenous administration, suggesting the absence of enzymes necessary to reduce the azide group into amine functionality. A-5-FP distributed slower to a similar apparent volume, and was cleared faster than 5-FC. The stereoselective pharmacokinetics of RCV was fully characterized in rats. Chiral inversion was not observed in vivo. Differences in plasma profiles between the two enantiomers were not readily visible. Nonetheless, the (+)-enantiomer had higher renal and nonrenal clearances, central and steady-state distribution volumes, and apparent absorption rate and extent. A weak enantiomeric interaction was detected, reducing steady-state distribution volume and slowing the absorption of both enantiomers. Nonlinear mixed effects modeling (NONMEM) was used to characterize allometric relationships describing differences in the disposition of the (-)-enantiomer of RCV, namely (-)-FTC, between 4 animal species. The initial model was deficient and mispredicted pharmacokinetic profiles and parameters in all species. When lower than expected clearance of (-)-FTC, and higher adipose tissue fraction in woodchuck were accounted for, predictions were enhanced appreciably. The estimates of allometric exponents for clearances and volumes were closely in agreement and not significantly different from the theoretical values of ¾ for functional properties like clearances, and 1 for structural properties like volumes. The model predicted the pharmacokinetic properties for a 70-kg man to be 27.7 and 21.5 L/h for total and distributional clearances, and 40.3 and 32.8 L for central and peripheral volumes, respectively. The accuracy of such predictions remains to be verified.
dc.subjectStereoselective pharmacokinetics
dc.subjectMixed effects
dc.subjectAllometric scaling
dc.titleThe pharmacokinetics, stereoselectivity and allometric scaling of fluorinated cytosine analogues
dc.description.departmentPharmaceutical and Biomedical Sciences
dc.description.majorPharmacy (Pharmaceutics)
dc.description.advisorF. Douglas Boudinot
dc.description.committeeF. Douglas Boudinot
dc.description.committeeAnthony C. Capomacchia
dc.description.committeeDANIEL B. HALL
dc.description.committeeD. Robert Lu
dc.description.committeeJames T. Stewart

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