BILIARY EXCRETION AND BLOOD/PLASMA RATIO OF NOVEL 5-BROMO-6-ALKOXY-5,6-DIHYDRO PRODRUGS OF 5-ETHYL-2\'-DEOXYVRIDINE

The biliary excretion and blood/plasma ratios of four novel 5-bromo-6-alkoxy- 5,6-dihydro prodrugs to S-ethyl-2'-deoxyuridine (EDU) including (-)-trans-(5S, 6S)-S-bromo-S-ethyl-6-methoxy-S, 6-dihydro-2'-deoxyuridine (BMEDU), (+ )-trans( SR, 6R)-S-bromo-S-ethyl-6-ethoxy-S, 6-deoxyuridine (BEEDU), (+ )-trans-(SR, 6R)-5-bromo-5-ethyl-6-ethoxy -S, 6-dihydro-S '-O-valeryl-2 ':.deoxyuridine (VBEEDU) and (+)-trans-(SR, 6R)-S-bromo-S-ethyl-6-ethoxy-S, 6-dihydro-5, 6- dihydro-3', S'-di-O-valeryl-2'-deoxyuridine (DVBEEDU) were determined using [4-14C]-labelled compounds. Liver samples taken following iv injection of 126 kBq (3.4IlCi) of these [4-14C]-labelled S,6-dihydro prodrugs into the tail vein of male Balb-C mice showed a higher percentage of the injected radioactivity than blood samples. A substantial amount of radioactivity was present in the large intestine, small intestine and gallbladder. Intestinal samples collected at longer post injection times showed a higher percentage of the injected dose relative to earlier post injection times. Bile samples collected at 8 min post injection of [4-14C]-labelled BMEDU, BEEDU, VBEEDU and DVBEEDU contained the highest radioactivity levels. Excretion of radioactivity in rat bile following a jugular vein injection showed a biexponential decline, but the radioactivity excretion rates in bile for all four compounds investigated were quantitatively similar. Accumulation of radioactivity in rat bile samples collected after injection of [4_14C]-BEEDU was substantially higher than that for [4_14C]-BMEDU, [4_14C]_VBEEDU and [4_14C]-DVBEEDU. The distribution of radioactivity in rat whole blood and plasma samples taken at the same post injection times were substantially different. It was postulated that the rate of conversion of the S, 6-dihydro prodrug to EDU is the main determinant of the whole blood/plasma ratio.