Biomedical subjects
Publications and source records attributed to C K Chu.
An efficient and practical method for the synthesis of (4R,5R)-4,5-O-isopropylidene-cyclopent-2-enone was developed from D-ribose by using a ring-closing metathesis reaction.
The pharmacokinetics of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZddU, CS-87), active anti-HIV compounds, were characterized in uninfected mice. Sensitive and specific HPLC techniques were used to quantitate AZT and AZddU concentrations in serum and brain homogenates following iv doses of 50 mg/kg and 250 mg/kg. The pharmacokinetic parameters of t1/2, CIt, and Vss were similar for both compounds at each dose; however, CIt and Vss decreased at the higher dose, indicating a dose dependency. At the 50 mg/kg doses, the CIt of AZddU and AZT was 1.27 liters/hr/kg and 1.38 liters/hr/kg, respectively, which is analogous to the clearance value of AZT observed in humans. Brain/serum concentration ratios for AZddU tended to be greater than those obtained for AZT and were significantly different at the 50 mg/kg dose, being 0.234 +/- 0.282 for AZddU and 0.064 +/- 0.025 for AZT.
3'-Azido-2',3'-dideoxy-5-methylcytidine (AzddMeC, CS-92), a nucleoside analog with structural similarities to both 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), has been shown to be a potent and selective inhibitor of human immunodeficiency virus type 1 in vitro. The pharmacokinetics of AzddMeC were characterized following intravenous and oral administration of 60 mg/kg of the compound to male rhesus monkeys. AZT was found to be a major metabolite of AzddMeC in monkeys. AzddMeC concentrations in serum declined rapidly in a biexponential fashion with the terminal half-life ranging from 0.5 to 1.3 hr. Total clearance of AzddMeC was 2.00 +/- 0.41 liters/hr/kg (mean +/- SD) with the fraction of AzddMeC metabolized to AZT of 0.32 +/- 0.05. Renal excretion of unchanged nucleoside and metabolic deamination yielding AZT were the primary routes of AzddMeC clearance. No glucuronide metabolite of AzddMeC was detected in urine samples, although, AZT-glucuronide was found in urine. The volume of the central compartment of AzddMeC was 0.53 +/- 0.28 liters/kg, the volume of the tissue compartment was 0.37 +/- 0.29 liters/kg, and the steady-state volume of distribution was 0.90 +/- 0.55 liters/kg. Volume of distribution values indicate that AzddMeC distributes extravascularly. The first-order oral absorption rate constant was 0.53 +/- 0.56 hr-1, and oral bioavailability was 26 +/- 13%. Thus, the rate of absorption of AzddMeC after oral administration was variable, and oral bioavailability was incomplete.