Prodrug for bioreductive activation-independent delivery of menahydroquinone-4: human liver enzymatic activation and its action in warfarin-poisoned human liver. Export

@article{citeulike:625185, abstract = {The N,N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; 1,4-bis, 3) were established in previous reports as prodrugs that could achieve the systemic bioreductive activation-independent delivery of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4), in rat. The present study was undertaken to investigate if the prodrugs could undergo cleavage to parent drug (MKH) by a human tissues enzyme catalyzed hydrolytic pathway, the mechanism of the prodrugs for vitamin K-dependent carboxylation in human liver and their action in the warfarin poisoned human liver. The hydrolysis of the esters was shown to be catalyzed by esterases located in human liver but not in human plasma. The susceptibility of the esters to undergo human liver esterase hydrolysis was affected by the esterified position: 1>2>3. By using a human liver microsomal test system, the stimulation of vitamin K-dependent carboxylation with the prodrugs was determined. The prodrug could stimulate the carboxylation activity in the absence of dithiothreitol, an artificial activator of the reductive activation pathway of MK-4. The carboxylation activity of the prodrug was strongly inhibited in the presence of eserine, an esterase inhibitor. The prodrug could also stimulate the carboxylase under warfarin-poisoned conditions, where the vitamin K cycle was strongly inhibited. The results confirmed that the prodrug could generate MKH in human liver (active site), and that the resultant MKH could act as a cofactor for the carboxylase without reductive activation processes of MK-4 to MKH. Such bioreductive activation-independent vitamin K-dependent carboxylation characteristic of the prodrug leads to enhanced pharmacological efficacy in the treatment of hypoprothrombinaemia induced in patients with coumarin and cephalosporin therapies.}, address = {Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.}, author = {Takata, J. and Karube, Y. and Hanada, M. and Matsunaga, K. and Iwasaki, H.}, citeulike-article-id = {625185}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/10077437}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=10077437}, issn = {0918-6158}, journal = {Biol Pharm Bull}, keywords = {prodrug, vitamink}, month = {February}, number = {2}, pages = {172--178}, posted-at = {2006-05-12 14:56:38}, priority = {0}, title = {Prodrug for bioreductive activation-independent delivery of menahydroquinone-4: human liver enzymatic activation and its action in warfarin-poisoned human liver.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/10077437}, volume = {22}, year = {1999} }

TY - JOUR ID - citeulike:625185 L3 - citeulike-article-id:625185 N2 - The N,N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; 1,4-bis, 3) were established in previous reports as prodrugs that could achieve the systemic bioreductive activation-independent delivery of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4), in rat. The present study was undertaken to investigate if the prodrugs could undergo cleavage to parent drug (MKH) by a human tissues enzyme catalyzed hydrolytic pathway, the mechanism of the prodrugs for vitamin K-dependent carboxylation in human liver and their action in the warfarin poisoned human liver. The hydrolysis of the esters was shown to be catalyzed by esterases located in human liver but not in human plasma. The susceptibility of the esters to undergo human liver esterase hydrolysis was affected by the esterified position: 1>2>3. By using a human liver microsomal test system, the stimulation of vitamin K-dependent carboxylation with the prodrugs was determined. The prodrug could stimulate the carboxylation activity in the absence of dithiothreitol, an artificial activator of the reductive activation pathway of MK-4. The carboxylation activity of the prodrug was strongly inhibited in the presence of eserine, an esterase inhibitor. The prodrug could also stimulate the carboxylase under warfarin-poisoned conditions, where the vitamin K cycle was strongly inhibited. The results confirmed that the prodrug could generate MKH in human liver (active site), and that the resultant MKH could act as a cofactor for the carboxylase without reductive activation processes of MK-4 to MKH. Such bioreductive activation-independent vitamin K-dependent carboxylation characteristic of the prodrug leads to enhanced pharmacological efficacy in the treatment of hypoprothrombinaemia induced in patients with coumarin and cephalosporin therapies. IS - 2 JF - Biol Pharm Bull SN - 0918-6158 AD - Faculty of Pharmaceutical Sciences, Fukuoka University, Japan. EP - 178 TI - Prodrug for bioreductive activation-independent delivery of menahydroquinone-4: human liver enzymatic activation and its action in warfarin-poisoned human liver. VL - 22 SP - 172 KW - prodrug KW - vitamink AU - Takata, J AU - Karube, Y AU - Hanada, M AU - Matsunaga, K AU - Iwasaki, H PY - 1999/02// UR - http://view.ncbi.nlm.nih.gov/pubmed/10077437 ER -