The aim of this study was to determine whether the derivatives of
ursodeoxycholic acid (UDCA) are useful compounds for clinical medicine. 1-1) A conjugate (5-ASA-UDCA monophosphate) of UDCA monophosphate with
5-aminosalicylic acid (5-ASA) was newly synthesized, and basic studies on this compound were carried out. This compound was efficiently deconjugated by
cholylglycine hydrolase (CGH) to release 5-ASA, whereas it was completely resistant to deconjugation by pancreatic and intestinal mucosal
enzymes. In animal experiments, the urinary excretion of N-acetyl-5-ASA (Ac-5ASA) was measured for 24 h following the
oral administration of 20 mg of 5-ASA-UDCA monophosphate. Control rats excreted 276.3 +/- 89.0 micrograms (mean +/- S.E.) of Ac-5ASA whereas rats with intestinal bacterial overgrowth excreted more (1224.1 +/- 231.5 micrograms; p < 0.01). These basic studies indicate that this compound is likely to offer a simple method for the evaluation of intestinal microorganisms without the use of
radioisotopes or expensive, special apparatus. 1-2) The disulphate
ester of ursodeoxycholyl-
p-aminobenzoic acid (
PABA-UDCA) was synthesized and compared with
PABA-UDCA for its use in the detection of intestinal bacteria. This compound,
PABA-UDCA disulphate, had characters in common with
PABA-UDCA in that it was deconjugated by CGH to release free
PABA. Further, in rat experiments the urinary excretion of
PABA was measured for 6 h after
oral administration of 15 mg
PABA-UDCA disulphate. Ten control rats excreted 188.2 +/- 13.6 micrograms (mean +/- S.E.) of
PABA; 10 rats with an intestinal stagnantloop excreted more (530.1 +/- 30.1 micrograms; p < 0.001): whereas 10 rats in each of three groups pretreated with
oral administration of various
antibiotics excreted less.
PABA-UDCA disulphate is a single pass type substance in the gut and its
oral administration test reflects the sum of the activities of bacteria in the small intestine and colon. From the results the obtained
PABA-UDCA disulphate was considered a good material to detect intestinal bacteria. 2) A conjugate (Lys-UDCA) of UDCA with
L-lysine was newly synthesized. In the incubation experiments with plasma, homogenates of the liver and small intestine, various pancreatic
enzymes and CGH, Lys-UDCA was deconjugated by
carboxypeptidases B and CGH. In the experiment using rodent everted gut sac, Lys-UDCA was actively absorbed from the terminal ileum. Lys-UDCA was recovered well in the bile after intravenous or intraileal administration of Lys-UDCA in
biliary fistula rat. These data suggest that Lys-UDCA is a good
prodrug of UDCA for
intravenous administration. 3) A novel
calcium-
chelating agent, N"-ursodeoxycholyl-
diethylenetriamine-N,N,N'-triacetic
acid (
UDCA-DTTA), was synthesized to study its ability to dissolve calcified
gallstones. In the presence of the agent, sliced human
gallstone with a composition of more than 50%
calcium bilirubinate was thoroughly dissolved, indicating that
calcium bilirubinate was dissolved from the
gallstone. The ability to dissolve
calcium was comparable to that of
EDTA. However, the laminar structure of the sliced
gallstone did not disappear in the presence of
EDTA, whereas the structure disappeared in the presence of
UDCA-DTTA. These results indicate that
UDCA-DTTA is an interesting compound as a parent substance for developing a
prodrug for an oral or intravenous agent to dissolve
calcium-containing
gallstones.