Pharmacokinetics, tissue distribution and excretion of a new photodynamic drug deuxemether.
Deuxemether was a new photodynamic drug effective for many kinds of solid tumor therapy, which was mainly composed of 3-(or 8-)-(1-methoxyethyl)-8-(or 3-)-(1-hydroxyethyl)-deutero-porphyrin IX (MHD) and 3,8-di(1-methoxyethyl)-deuteroporphyrin IX (DMD). The aims of this study were to elucidate its pharmacokinetic characteristics, tissue distribution, plasma protein binding and excretion properties and underlying mechanisms of deuxemether in rats based on the simultaneous determination of MHD and DMD. The pharmacokinetic profiles of both MHD and DMD in rats after intravenous doses were linear and best fitted to a two compartment model, characterized with a rapid distribution phase (MHD: t(1/2)alpha, 0.09-0.14 h; DMD: t 1/2 alpha, 0.07-0.11h) and a relatively slow elimination phase (MHD: t 1/2 beta, 2.03-3.20 h; DMD: t 1/2 beta, 2.51-3.20 h). The tissue distributions of MHD and DMD in rats were rather limited as evidenced from their low distribution volume (0.75-1.70 L/kg) and the results of tissue distribution study. Protein binding of MHD and DMD were moderate (65.36-89.99% for MHD; 45.43-76.23% for DMD), independent of drug concentrations and similar between human and rat plasma over a concentration range of 0.50-50.0 microg/mL. Both MHD and DMD were predominantly (>74.1%) eliminated from rats as the parent drugs through the hepatobiliary systems and finally excreted into the feces. The multidrug resistance-associated proteins 2 (MRP2) inhibitors, bromosulfophthalein and probenecid, substantially inhibited the hepatobiliary elimination of MHD and DMD while the P-gp inhibitor digoxin had little effect, suggesting that MRP2 may contribute to the rapid and extensive hepatobiliary excretion of deuxemether. There were no significant differences between MHD and DMD for all pharmacokinetic characteristics studied. In conclusion, this study provided firstly the full pharmacokinetic characteristics and mechanisms of deuxemether, which would be helpful for its clinical regiment design.
Wang
Rui
R
Key Laboratory of Drug Metabolism and Pharmacokinetics, 24 Tong Jia Xiang Street, Mail Box 210, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Hao
Haiping
H
Wang
Guangji
G
Xie
Haitang
H
Xu
Meijuan
M
Wang
Wei
W
He
Hui
H
Li
Xiaoyu
X
D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D003905:Deuteroporphyrins / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D004077:Digoxin / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents / Q000008:administration & dosage / Q000494:pharmacology; D007260:Infusion Pumps; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology; D011524:Protoporphyrins / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution; D014528:Uricosuric Agents / Q000008:administration & dosage / Q000494:pharmacology
D001798:Blood Proteins; D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D014528:Uricosuric Agents; C532157:deuxemether; D013448:Sulfobromophthalein; D004077:Digoxin; D011339:Probenecid