The present study was divided between two different drug delivery goals, each involving naltrexone (NTX) or its active metabolite, 6-β-naltrexol (NTXOL). First, amino acid esters of NTX and NTXOL were prepared in order to test their candidacy for microneedle-enhanced transdermal delivery. Second, a 3-O-(-)-cytisine-naltrexone (CYT-NTX) codrug was prepared for screening as a potential oral delivery form of NTX and (-)-cytisine (CYT). The amino acid prodrugs were intended for the treatment of alcohol abuse, while the codrug was designed as a single agent for the treatment of alcoholism and tobacco-dependency co-morbidities. One hypothesis of this work was that prodrugs of NTX or NTXOL can be designed that possess superior skin transport properties through microneedle-treated skin compared to parent NTX or NTXOL. Nine amino acid ester prodrugs were prepared, and only three 6-O amino acid ester prodrugs of NTXOL were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. 6-O-β-Ala-NTXOL, the lead compound, exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1 h); however, this in vitro stability value indicates that the prodrug may require hepatic enzyme-mediated hydrolysis for sufficiently rapid bioconversion to NTXOL in vivo. A second hypothesis of this work was that a CYT-NTX codrug could be designed with appropriate stability characteristics for oral delivery. CYT-NTX was found to be stable over the time course of 24 h in buffer systems of pH 1.5, 5.0, 7.4 and 9.0, and in 80% rat plasma, 80% human plasma, simulated gastric fluid and simulated intestinal fluid. Six (3 rats/group) Sprague-Dawley male rats were dosed i.v. with 1 mg/kg CYT-NTX codrug, or 10 mg/kg, p.o. Oral administration of a 10 mg/kg dose of CYT-NTX codrug resulted in rapid absorption and distribution (5 min) of CYT-NTX codrug, and NTX was released from codrug with a peak plasma concentration of 6.8 ± 0.9 nmol/L reached within 65 minutes. Plasma CYT was not detected; however, NTX delivery was achieved with a fraction absorbed value of 13%. Thus, CYT-NTX may hold promise as a potential oral codrug for further optimization and development.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:pharmacy_etds-1014 |
| Date | 01 January 2013 |
| Creators | Eldridge, Joshua A. |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Pharmacy |
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