The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FIC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at a phase of 4.7 + 1.1 min (mean ± standard deviation) and a half-life at 13 phase of 44 ± 8.8 min (n = 5). The total body clearance of FTC was 1.8 ± 0.1 liters/h/kg, and the oral bioavailablity was 90%o ± 8%.The volume of distribution at steady state (Vss) was 1.5 ± 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 ± 0.2 liters/kg/h, lowered the Vss to 1.2 ± 0.2 liters/kg, and reduced the oral bioavailablity to 65% ± 15%. FPTC in the brains of rats was initiaHly less than 2% of the plasma concentration but increased to 6%o by 2 h postdose. Probenecid elevated levels of FEC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% ± 3% and 5% ± 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70%o ± 2.5% and 25% ± 1.6%. Two sulfoxides of FEC were observed in the urine, accounting for 0.4% ± 0.03% and 2.7% ± 0.2% of the intravenous dose and 0.4o% ± 0.06% and 2.5% ± 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% ± 0.06% of the intravenous dose and 0.4% ± 0.07%6 of the oral dose, and FEC glucuronide, representing 0.7% ± 0.2% of the oral dose and 0.4% ± 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.

(2'R, 5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 0.02 liter/kg. The terminal elimination half-life was 1.0 + 0.2 h. The absolute bioavailability after oral dosing was 63% + 4% at 10 mg/kg.Concentrations of 524W91 in the cerebrospinal fluid were 4% 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% + 6% of the radioactive dose in the 0-to 72-h urine, 33% + 10% in the feces, and 10% 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The major urinary metabolite was a 3'-sulfoxide, constituting 27% of the radiolabeled material in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% 7% of the radiolabel in the 0-to 48-h urine. Small amounts of the 3'-sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.

The aim of our study was to design and evaluate Amlodipine transdermal patches using polymers such as ethyl cellulose. Matrix type transdermal patches containing Amlodipine were prepared by solvent casting method by using polymers like ethylcellulose 1 %, 1.5 %, 2 % and 2.5 % and a total of eight formulations were prepared. Plasticizers used were propylene glycol and dibutylpthalate. The transdermal patches were evaluated for their physicochemical properties like folding endurance, thickness, percentage moisture loss, percentage moisture absorption, drug content and water vapour transmission rate. The diffusion studies were performed by using franz diffusion cell. Formulation E6 (1.5 % Ethylcellulose with dibutylphthlate) as plasticizers showed a maximum release of 99 % in 24 hours. Out of these eight formulations of EC, 1.5 % Ethylcellulose (E6) was optimized since they produced a sustained and a complete release over a period of 24 hours. Thus the knowledge on the use of ethyl cellulose to control drug release in transdermal delivery systems might be applicable to other transdermal drug delivery system as well.