In vitro and in vivo investigations of dihydropyridine-based chemical delivery systems for anticonvulsants.
A dihydropyridine-based chemical delivery system (CDS), intended to improve drug delivery to the brain, was investigated with a series of analogues of the anticonvulsant striripentol. In vitro experiments demonstrated that the rates of hydrolysis of the corresponding pyridinium conjugates were influenced markedly by small changes in the structure of the drug moiety to be released. Thus, allylic esters were hydrolyzed rapidly to drug in all aqueous media, while the analogous saturated esters and an allylic amide derivative were almost totally stable. The mechanism of hydrolysis, which is particular to this series of CDS conjugates, appeared to occur via ionization to a resonance-stabilized carbocation intermediate. The same CDS compounds were investigated in vivo and compared to the corresponding drugs after intravenous administration. Only those CDS compounds that were found to hydrolyze in vitro released appreciable amounts of drug in vivo. Prolonged release of the drug from the CDS in the brain could be demonstrated for these compounds, but the gain in the ratio of brain-to-plasma AUC when the CDS was administered depended on the innate distribution characteristics of the drug. Thus, the drug D3, which had a high brain-to-plasma AUC ratio, did not show an improvement in this ratio when administered as CDS3. In contrast, stiripentol with a poor brain-to-plasma AUC ratio showed a two- to threefold increase in this ratio when administered as a CDS. These investigations highlight the need for a thorough understanding of the mechanism of drug release and the importance of the pharmacokinetic properties of the drug in designing a carrier system for delivery of drugs to the brain.
Boddy
A V
AV
Department of Pharmaceutics, University of Washington, Seattle 98195.
Zhang
K
K
Lepage
F
F
Tombret
F
F
Slatter
J G
JG
Baillie
T A
TA
Levy
R H
RH
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D001921:Brain / Q000187:drug effects*; D004095:Dihydropyridines / Q000008:administration & dosage*; D004148:Dioxolanes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D015195:Drug Design; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000927:Anticonvulsants; D004095:Dihydropyridines; D004148:Dioxolanes; C038806:1,4-dihydropyridine; C021092:stiripentol