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The disposition of 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N- [2-(diethylamino)ethyl] benzamide hydrochloride (ML-1035) following intravenous (10 mg kg-1) and oral (200 mg kg-1) dosing was investigated in male and female New Zealand white rabbits. After intravenous dosing ML-1035 was eliminated with a half-life of 1.45 +/- 0.49 h in males and 0.79 +/- 0.08 h in females. Volume of distribution at steady-state was 2.08 +/- 0.98 l kg-1 in males and 9.11 +/- 5.86 l kg-1 in females. Clearance averaged 2.99 +/- 1.11 l h-1 kg-1 in males and 16.73 +/- 7.29 l h-1 kg-1 in females. All pharmacokinetic parameters were significantly different between males and females (p < 0.05). Absolute bioavailability after oral administration was 7.35 per cent for males and 12.31 per cent for females, suggesting that ML-1035 undergoes significant first-pass elimination. Plasma area under the curve for the metabolites of ML-1035 after both oral and intravenous administration were also different between the two sexes. These data suggest that the disposition of ML-1035 shows significant differences between male and female rabbits.

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The mass balance of 14 C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague±Dawley rats after single oral doses of 1´0 g kg 71 . Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95´8+5´30% bismuth dose, while 99´2+3´63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0´051+0´028% bismuth dose, and 1´83+1´08% radioactive dose. Biliary excretion of bismuth averaged 0´0003+0´0006% bismuth dose, and 0´026+0´030% radiolabeled dose. An average 0´005+0´002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quanti®able limits. Though BISOS contains 57´3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (C max for BISOS averaged 110+55´4 mg eq mL 71 , while for bismuth it was 26´1+10´3 ng mL 71 ). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits dierential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration.