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 iv 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 C(max) of (-)CBV after a 40 mg/kg oral dose of (-)6AC was 1.65 ± 0.7 μg/ml as compared with the previously reported C(max) of 1.00 μg/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.
|Original language||English (US)|
|Number of pages||5|
|Journal||Drug Metabolism and Disposition|
|State||Published - 1992|