Improvement of aqueous solubility and rectal absorption of 6-mercaptopurine by addition of sodium benzoate.
The solubility of 6-mercaptopurine (6-MP) in water increased as the concentration of sodium benzoate or sodium hippurate in the solution increased. The solubility of 6-MP in 20% (w/v) sodium benzoate or sodium hippurate solution was about 6-fold larger than that of 6-MP alone. The stability constant of the soluble complex of 6-MP with sodium benzoate was estimated to be 2-8 M-1 from (1) phase-solubility study and (2) analysis of chemical shifts observed in 1H-NMR. Partition of 6-MP from the saturated solution to n-octanol was also greatly increased by the addition of sodium benzoate or sodium hippurate, the degree being less in the latter. Administration of 6-MP with 20% (w/v) sodium benzoate to rat rectum resulted in enhanced absorption and the area under the plasma concentration-time curve was comparable to that obtained by intravenous administration (bioavailability = 100%), while the bioavailability after intrarectal administration of 6-MP with 20% (w/v) sodium hippurate was only 9%. The reason for the difference was discussed.
Takeichi
Y
Y
Pharmaceutical Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Kimura
T
T
D020003:1-Octanol; D000285:Administration, Rectal; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D019817:Benzoic Acid; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006626:Hippurates / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015122:Mercaptopurine / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000442:Octanols / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000187:drug effects / Q000378:metabolism*; D012995:Solubility; D014867:Water
D001565:Benzoates; D006626:Hippurates; D000442:Octanols; D014867:Water; D019817:Benzoic Acid; D015122:Mercaptopurine; D020003:1-Octanol; C030514:hippuric acid