Hydrolysis of dinitrobenzamide phosphate prodrugs: the role of alkaline phosphatase.
Phosphate prodrugs which undergo hydrolysis in vivo have been used to improve the solubility and pharmacokinetic properties of a number of drugs. Dinitrobenzamide mustards (DNBM) are examples of such drugs. We investigated the ability of purified alkaline phosphatase isoforms to dephosphorylate three DNBM phosphate prodrugs. In addition, the relative rate of dephosphorylation of these phosphate prodrugs in a number of tissues was determined. These phosphate prodrugs are indeed substrates for alkaline phosphatase, with time dependent formation of the hydrolysis product. Intestinal alkaline phosphatase (IAP) and placental alkaline phosphatase (PLAP) had the highest activity for these substrates and compound P2 was the most rapidly metabolised. Similarly, compound P2 had the shortest half life in mouse serum (t1/2 = 1.15 h) compared with P1 (t1/2 = 13.34 h) and P3 (t1/2 = 4.4 h). However, serum has very low dephosphorylase activity for these substrates compared with intestine and liver homogenates. In addition, there is little or no difference in the relative rate of dephosphorylation of each of the three compounds in mouse tissues in contrast to the pattern observed with purified alkaline phosphatase and mouse serum. Hence additional phosphatase enzymes may be involved in the metabolism of phosphate prodrugs in vivo.
Lo
Wing-Yee
WY
Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.
Balasubramanian
Amit
A
Helsby
Nuala A
NA
D000469:Alkaline Phosphatase / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007527:Isoenzymes / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics*; D010766:Phosphorylation / Q000187:drug effects; D011355:Prodrugs / Q000493:pharmacokinetics*
D001549:Benzamides; D007527:Isoenzymes; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D000469:Alkaline Phosphatase