Chemical delivery systems for some penicillinase-resistant semisynthetic penicillins

Chemical delivery systems (CDS's) based on a dihydropyridine----quaternary pyridinium ion redox system analogous to the naturally occurring NADH----NAD+ system were synthesized for a group of staphylococcal penicillinase resistant penicillins, including methicillin, oxacillin, cloxacillin, and dicloxacillin, in order to improve their penetration of the central nervous system (CNS). The CDS's are penicillin monoesters of gem-diols in which the other hydroxyl group is esterified by the dihydrotrigonelline carrier. The CDS's were found to be much more lipopholic than the parent drugs by comparing their log k' values used as lipophilicity indexes. A study of the chemical oxidation of the CDS's performed by a UV spectrophotometric method showed relatively slow reaction. Stability studies were performed in buffers and different animal tissues for both the CDS's and the quaternary salt type derivatives. These studies showed that the CDS's were oxidized to the quaternary salt forms at neutral and basic pH and added water at lower pH. The quaternary salts released the parent drugs both in buffers and in vitro. A preliminary in vivo distribution study in the rat and rabbit demonstrated blood-brain barrier (BBB) penetration by the CDS, whereas no drug was detected by administering the drug itself.