Pharmacokinetic evaluation of (-)-6-aminocarbovir as a prodrug for (-)-carbovir in rats.
The recently synthesized carbocyclic 2',3'-didehydro-2',3'-dideoxy-6-deoxy-6-amino-guanosine [(-)6AC] was evaluated as a prodrug for carbovir, carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine [(-)CBV] in seven male Sprague-Dawley rats. A randomized three-way cross-over design was used. Rats were assigned to receive the following treatments: a 20 mg/kg (-)6AC infusion, 40 mg/kg (-)6AC orally, and a 20 mg/kg (-)CBV infusion. Blood samples were collected over 480 min, and urine was collected for up to 48 hr. A 2- to 3-day washout period was observed between treatments. Following i.v. infusion, (-)6AC concentrations in the blood declined rapidly in a monoexponential pattern with an elimination half-life of 11.3 +/- 3.3 min (mean +/- SD, n = 7). The time-averaged total body clearance was 115.7 +/- 32.6 ml/min/kg. The fraction of the dose excreted unchanged in urine was 0.28 +/- 0.06. The fraction of the (-)6AC dose metabolized to (-)CBV was 0.48 +/- 0.14. Following oral administration of (-)6AC, the bioavailability of (-)CBV was 46.2 +/- 9.9% (n = 6) in comparison with the bioavailability of approximately 20% previously obtained after an oral dose of (-)CBV. The Cmax of (-)CBV after a 40 mg/kg oral dose of (-)6AC was 1.65 +/- 0.7 micrograms/ml as compared with the previously reported Cmax of 1.00 microgram/ml obtained after a 60 mg/kg oral dose of (-)CBV. (-)6AC has considerable potential for the improvement of the extent of absorption of (-)CBV from oral dosing.
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
C L
CL
Zimmerman
R P
RP
Remmel
S S
SS
Ibrahim
S A
SA
Beers
R
R
Vince
D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001682:Biological Availability; D015224:Dideoxynucleosides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; C057503:carbovir; C069735:6-aminocarbovir