Naslov
Utjecaj različitih soli visoko permeabilne slabe baze doksazosina na oralnu apsorpciju
(Effects of salt forms on the oral absorption of high permeable weak base doxazosin)

Autori
Erceg, Marijana

Vrsta, podvrsta i kategorija rada
Ocjenski radovi, doktorska disertacija

Fakultet
Farmaceutsko-biokemijski fakultet

Mjesto
Zagreb

Datum
08.12

Godina
2011

Stranica
124

Mentor
Reppas, Christos ; Cetina-Čižmek, Biserka

Ključne riječi
doxazosin base; doxazosin salts; absorption; early exposure; solubility; dissolution; dogs; humans

Sažetak
In this study, the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM) was evaluated. DB, DM, and doxazosin hydrochloride (DH) were prepared and extensively characterized. The solubility of prepared substances was tested in vitro in various media, including human aspirates, using the shake flask method. Dissolution experiments were performed in simple buffer media and biorelevant media simulating gastric and intestinal fluids in the fasted and fed state. Pharmacokinetic (PK) studies were performed in dogs with DB and DM tablets in the fasting and fed state, while the results form human PK study on DM tablets in the fasted state were available from previous Pliva´s study. Analytical method for determination of doxazosin in canine plasma was developed and validated using canine samples collected in the fed state in order to assure the suitability of the method for measurement of low concentrations of doxazosin in plasma and high specificity of the method despite the number of interfering compounds in the fed state plasma samples. Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid containing physiological components (FaSSGF-V2) but not by data in HClpH 1.8. Unlike data in FaSSGF-V2, dissolution of DB and DM tablets in HClpH 1.6 is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described modelling procedures, the cumulative doxazosin profile in plasma was simulated and the 0–2 h profile was used for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet administrations to 24 adults in fasting state, were constructed from corresponding actual plasma profiles. Compared with in vitro DM data in aqueous buffers, DM data in biorelevant media led to better prediction of early exposure. Based on intersubject variability in early exposure after DM administration and simulated profiles, the administered phase, DB or DM, does not have a significant impact on early exposure in fasting state. Early exposure in dogs (evaluated based on partial AUCs) was significantly higher after administration of DM to dogs. Therefore, dog is not a good model for predicting differences between DB or DM in the fasted state, but it may be a good model for predicting food effects and differences between DB and DM in the fed state.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

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