title: In vitro and in vivo study of water-soluble prodrugs of dexanabinol.
abstract: Trialkylammonium acetoxymethyl esters of dexanabinol were synthesized and evaluated as water-soluble prodrugs. Syntheses were performed by conventional methods; solubility in water and stability in buffers and human plasma were determined by HPLC, and in vivo tissue distribution studies were performed in a rat model. Most of the new derivatives were soluble in water (approximately 50 mg/mL). They were relatively stable in water, while rapidly hydrolyzed in human plasma. Distribution studies indicated that peak concentrations of drug both in blood (30 microg/mL) and brain (2 microg/mL) were rapidly (5 min) achieved after iv administration of a selected prodrug to rats. The blood concentration decreased faster than brain levels which were detectable even after 24 h. Some of the examined esters could be further developed as water soluble prodrugs of dexanabinol.
authors.affiliation: Pharmos Corporation and Alchem Laboratories Corporation, 13305 Rachael Boulevard, Alachua, Florida 32615, USA. emilpop@aol.com
authors.forename: E
authors.initials: E
authors.lastname: Pop
authors.forename: S
authors.initials: S
authors.lastname: Rachwal
authors.forename: J
authors.initials: J
authors.lastname: Vlasak
authors.forename: A
authors.initials: A
authors.lastname: Biegon
authors.forename: A
authors.initials: A
authors.lastname: Zharikova
authors.forename: L
authors.initials: L
authors.lastname: Prokai
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D004952:Esters / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D007275:Injections, Intravenous; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D004952:Esters; D018691:Excitatory Amino Acid Antagonists; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D013759:Dronabinol; C062018:HU 211