A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N‐phosphonooxymethyl prodrugs in rats and dogs

• Published in: Journal of pharmaceutical sciences 1999-09, Vol.88 (9), p.928-932
• Main Authors: Krise, Jeffrey P., Charman, William N., Charman, Susan A., Stella, Valentino J.
• Format: Article
• Language: English
• Subjects: Amines - administration & dosage; Amines - chemistry; Amines - pharmacokinetics; Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Biological Availability; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Cinnarizine - administration & dosage; Cinnarizine - chemistry; Cinnarizine - pharmacokinetics; Dogs; General pharmacology; Histamine H1 Antagonists - administration & dosage; Histamine H1 Antagonists - chemistry; Histamine H1 Antagonists - pharmacokinetics; Injections, Intramuscular; Injections, Intravenous; Loxapine - administration & dosage; Loxapine - chemistry; Loxapine - pharmacokinetics; Male; Medical sciences; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js980382v

N‐Phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half‐life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.