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Tissue distribution and metabolism studies for a series of barbiturates
Başlık:
Tissue distribution and metabolism studies for a series of barbiturates
Yazar:
Ballard, Peter G., author.
ISBN:
9780438083202
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (249 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Tissue partition coefficients and blood clearances are critical components of physiologically based pharmacokinetic models and can be estimated from in vivo or in vitro studies. However, there are problems associated with their estimation. The studies reported currently were designed to investigate and validate an in vitro method for determining tissue-to-plasma partition coefficients (Kp) for a series of 5-n-alkyl-5-ethyl barbituric acids and to compare the results with those from an optimal in vivo study, i.e. dosing by constant- rate i.v. infusion to steady state. The in vitro metabolism of the barbiturates was also estimated from rat liver microsomes. Tissue slices were observed to swell from approximately 0 to 40% for different tissues over the course of an in vitro incubation. As a consequence, corrections were made to the calculation of Kp to account for the amount of drug imbibed with medium and the-amount in the vascular compartment, resulting in a value representing the unbound extracellular tissue-to-plasma partition coefficients (Kpuc). A clear distinction in Kpue was observed between compounds restricted to extracellular space and those occupying total water space. Thus, an in vitro system for determining Kpue for drugs has been developed and validated for reference marker compounds known to occupy a specific tissue volume. In contrast to imbibed medium, albumin was observed to diffuse from tissue pieces during the incubation. For drugs highly bound to plasma albumin, this could substantially alter the observed partitioning. However, an expression was developed which indicated that this would not be the case for the 5-n-alkyl-5-ethyl barbituric acids. A mathematical model was also derived to describe the diffusion of albumin from tissue pieces. When applied to the experimental data, this model demonstrated that the diffusion coefficient of albumin ranged greatly in different tissues, with a maximal value close to that of albumin in water. The Kpue values of the 5-n-alkyl-5-ethyl barbituric acids were determined simultaneously from a continuous-rate i.v. infusion study in male rats and the results generally correlated well with those following i.v. bolus dosing and in vitro incubation. Kpue values increased with increasing barbiturate LogP, indicating the importance of lipophilicity in determining drug distribution. However, the in vitro Kpue values for the n-octyl and n-nonyl homologues underpredicted the in vivo results. A mathematical model was developed to describe the uptake of drug from medium to tissue during in vitro incubations and was used to predict an alternative design which was successful in reducing the time to reach equilibrium. Hepatic clearance of the n-pentyl to n-nonyl barbituric acids was predicted from in. vitro data in rat liver microsomes to within 20% of the in vivo results. It was found to be essential to account for microsomal binding of the highly bound barbiturates for an accurate estimation of clearance to be obtained. Incubating multicomponent mixtures of barbiturates in rat microsomes and hepatocytes indicated that the metabolism of individual components could be inhibited, thus precluding their use for predicting hepatic clearance. The studies reported currently have indicated the applicability of simple in vitro systems for producing data that are predictive of values observed in vivo.
Notlar:
School code: 1543
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(686869.1) | 686869-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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