Absolute bioavailability and disposition of (-) and (+) 2 '-deoxy-3 '-oxa-4 '-thiocytidine (dOTC) following single intravenous and oral doses of racemic dOTC in humans

The purpose of this study was to characterize the pharmacokinetics and dete rmine the absolute bioavailability of 2'-deoxy-3'-oxa-3'-thiocytidine (dOTC ) (BCH-10652), a novel nucleoside analogue reverse transcriptase inhibitor, in humans. dOTC belongs to the 4'-thio heterosubstituted class of compound s and is a 1:1 mixture of its two enantiomers, (-) and (+) dOTC, Twelve hea lthy adult male volunteers each received oral (800-mg) and intravenous (100 -mg) doses of dOTC in two study periods separated by at least 7 days, Sixte en plasma samples were obtained over 72 h and assayed for (-) and (+) dOTC, and the resultant data fit by candidate pharmacokinetic models. Data were weighted by the fitted inverse of the observation variance; model discrimin ation was by AIC, The pharmacokinetic model was a linear, three compartment model, with absorption occurring during one to three first-order input pha ses, each following a fitted lag time. The model goodness-of-fit was excell ent; r(2) ranged from 0.995 to 1.0, The mean absolute bioavailabilities of (+) and (-) dOTC were 77.2% (coefficient of variation [given as a percentag e] [CV%], 14) and 80.7% (CV%, 15), respectively, The median steady-state vo lume of distribution for (+) dOTC, 73.7 (CV%, 19.2) liters/65 kg, was great er than that for (-) dOTC, 51.7 (CV%, 16.7) liters/65 kg (P < 0.05), The me dian total clearance of(+) dOTC was less than that of (-) dOTC, 11.7 (CV%, 17.3) versus 15.4 (CV%, 18.6) liters/h/65 kg, respectively (P < 0.05), The intersubject variability of these parameters was very low. The median termi nal half-life of (+) dOTC was 18.0 (CV%, 31.5) h, significantly longer than the 6.8 (CV%, 69.9) h observed for (-) dOTC (P < 0.01). No serious adverse events were reported during the study. These results suggest that dOTC is well absorbed, widely distributed, and well tolerated, The terminal half-li ves indicate that dosing intervals of 12 to 24 h would be reasonable.