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Groups of rats were orally or dermally administered 14C-CS-1135 or 14C-AMP and absorption, distribution, metabolism and elimination determined. The orally administered CS-1135 was rapidly absorbed reaching Cmax within one hour and eliminated rapidly in urine. The rapid absorption was apparent from the drop in the dose from the GI tract within three hours between Cmax (56±10 to 68±9%) and ½Cmax (13±3 to 16±6%). Total urinary elimination accounted for 91-99% of the dose, most (77-92%) occurring within the first 48 hours. Fecal elimination accounted for only 4-8% of the dose. Absorption, distribution, and elimination of AMP was almost identical to CS-1135 with relatively faster absorption, reaching Cmax in <0.5 hour. Only 3-4% of the dose was found in tissues at the end of the study. Elimination of radioactivity from blood was biphasic with a rapid distributional (α) phase lasting for 24 hours for CS-1135 and 6 hours for AMP, followed by a slower elimination phase (β). The plasma t½ of the β phase of CS- 1135 was between 20 and 39 hr; females were slightly more efficient in elimination. The RBC t½ of the β phase of CS-1135 was slower (42-55 hours) indicating possible sequestration of radioactivity in RBCs. The administered CS-1135 was rapidly metabolized, apparently prior to reaching the systemic blood circulation. Out of 176 samples, parent CS-1135 was detected in only 10 samples without any specific pattern. AMP, one of the major metabolites of CS-1135, was detected in most of the blood samples. The AUC0→∝ of radioactivity in plasma and RBC was within dose proportionality between the low and high dose. The time-course decline of AMP derived radioactivity from plasma and RBC was almost identical to CS-1135 with slightly longer β elimination half-life. AMP was detected in the blood collected from the rats dosed with AMP at quite consistent concentrations found in rats dosed at an equimolar concentration of CS- 1135. Only the first three samples had ~2-fold higher AMP than was observed in CS-1135 dosed rats. There was an indication of sequestration of AMP to RBC. The majority (>80% in urine and ~8% in feces) of the orally administered radioactivity recovered in excreta from 14CCS- 1135 dosed rats was AMP and only one metabolite above 5% (6-7% in urine) of the administered dose. Urine of the 14C-AMP dosed rats contained only the parent compound.
Most of the dermally applied 14C-CS-1135 evaporated rapidly from the application site and recovered in the charcoal trap. Very little radioactivity was found in the dose site skin, averaging ≤1% of the dose with only ≤0.05% of the dose found in the stratum corneum. The total dermal absorption of 14C-CS-1135 was 13-15% of the dose. Out of which, ~11% was eliminated in urine, most (~8%) within 48 hours. Fecal elimination comprised <0.5% of the dose. The Cmax was reached within one hour post-dosing indicating rapid penetration. The difference in the AUC0→∝ between the two routes was 11 to 14-fold, consistent with the 13-15% dermal absorption compared to ~95% oral absorption. The AUC0→∝ of the dermally administered dose in RBC was 56-90% higher than plasma suggesting sequestration in RBCs. The elimination of radioactivity from blood was biphasic with a relatively slower α phase due to the presence of dose at the application site for six hours and its continuous penetration for some time after the removal/washing. The slope of the β phase was almost parallel to the oral group resulting in almost the same t½β for most of the rats. The total dermal absorption of 14C-AMP was ~43% of the dose. Twenty four percent of the total dose was eliminated in urine, most (~18%) within 48 hours. Fecal elimination was ~2%. Around 6% of the dose was found in tissues. It took much longer to reach Cmax after dermal application (~4 hours) than the oral dose (0.3 hour), indicating slower dermal penetration of AMP. The elimination of the radioactivity from blood was biphasic with relatively slower α phase. The t½β for most of the rats was similar between the two routes. The dermally applied radioactivity was eliminated slower (49% longer t½) from the RBCs than plasma, resulting in 44% higher AUC0→∝, an indication of sequestration of 14C-AMP derived radioactivity in RBCs, similar to that observed in the orally dosed group. Only AMP was detected in the urine of animals dosed dermally with 14C-CS-1135, accounted for 7-9% of the administered dose. Only AMP was detected in the urine of the rats dosed dermally with 14CAMP.
CS-1135 was rapidly hydrolyzed in whole blood, plasma and urine. The level of CS-1135 became undetectable in blood and plasma within 15 minutes after fortification to control samples. Similarly, CS-1135 was rapidly hydrolyzed in urine at room temperature.
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