Carbovir is a new carbocyclic nucleoside that has potent activity against the HIY in vitro. The compound has been selected by the NIH for Development as a promising drug for AIDS. We have recently developed an HPLC assay For carbovir and have studied the pharmacokinetics of carbovir after oral and intravenous administrations to rats. The bioavaibility if carbovir was on)y 11.7+4.7%. To improve the oral absorption of carbovir. we propose to synthesize and evaluate several classes of carbovir prodrugs. A second major goal of a prodrug strategy is to increase penetration into the CNS. AIDS patients have many reurologicai problems that may be directly due to an HIV brain infection. Four classes of prodrugs will be synthesized: 1) Several 5'-0H esters; 2) Lipophilic carbovir monophosphate esters (carbovir-diphosphate- L-dipalmitin) and bis(acyloxymethyl) esters of carbovir- morphosphate: 3a.) 6-amino-carbovir (adenosine deaminase activated), 3b.) 6-deoxy-carbovir(xanthine oxidase activated 4) Dihydropyridine/ pyridinium esters for selective CNS uptake. Systematic aviator will be done to the follow) experiments: 1) In vitro metabolism with serum, liver, brain, or intestinal enzyme preparations. 2) Determination of the bioavaibility of selected Prodrugs compared to carbovir tn animals. 3) Examination of CNS peretratical if carbovir and its prodrugs. 4) Determination of the site of pre-systemic metabolism of the prodrugs with an intestinal- liver perfusion model system. The methods developed for carbovir prodrugs may also be used with other promising antiviral nucleosides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028236-02
Application #
3142589
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Pharmacy
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zimmerman, C L; Wen, Y; Remmel, R P (2000) First-pass disposition of (-)-6-aminocarbovir in rats: II. Inhibition of intestinal first-pass metabolism. Drug Metab Dispos 28:672-9
Wen, Y; Remmel, R P; Zimmerman, C L (1999) First-pass disposition of (-)-6-aminocarbovir in rats. I. Prodrug activation may be limited by access to enzyme. Drug Metab Dispos 27:113-21
Zimmerman, C L; Wen, Y; Soria, I et al. (1997) Evaluation of gastrointestinal absorption and metabolism. Drug Metab Rev 29:957-75
Zimmerman, C L; Remmel, R P; Ibrahim, S S et al. (1992) Pharmacokinetic evaluation of (-)-6-aminocarbovir as a prodrug for (-)-carbovir in rats. Drug Metab Dispos 20:47-51
Remmel, R P; Huang, S H; Hoff, D et al. (1990) Improved fluorometric high-performance liquid chromatographic assay for (-)-carbovir in rat blood and urine. J Chromatogr 534:109-18