2006 - Brugge/Bruges - Belgium

PAGE 2006: Applications- Other topics
Elsa López Pintor

Population pharmacokinetics approach for salbutamol sulphate in rats

Lopez-Pintor E (1), Valenzuela B (1), Montesinos A (2), Martín-Villodre A (2), Casabó V.G (2)

(1) Pharmacy and Pharmaceutics Division, Department of Engineering, Faculty of Pharmacy, Miguel Hernández University, Spain.(2) Department of Pharmacy and Pharmaceutics, Faculty of Pharmacy, University of Valencia, Burjassot (Valencia), Spain.

Introduction: Salbutamol sulphate is a b-2-adrenergic agonist widely used in the treatment of asthmatic disorders and chronic obstructive lung diseases. The absolute oral bioavailability of salbutamol when administered in conventional dosage forms has shown to be incomplete, variable and rather irregular [1]. Pre-systemic interactions with P-glycoprotein (P-gp) together with metabolism via intestinal sulphation have been argued as a potential explanation for salbutamol sulphate poor oral bioavailability [2]. Previous studies performed using in situ absorption Dolusio method confirms that this poor bioavailability could be due to P-gp secretory system. However, the nature of the Doluisio model is that the drug solution is exposed to the same surface of the intestine repeatedly and some authors suggest that the likely contribution of P-gp may be overestimated by employing a recirculatory model of this nature.

Objective: The aim of the present study is to determine the oral bioavailability of salbutamol sulphate in rat and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following intravenous (IV), intraperitoneal (IP) and oral doses.

Methods: A pharmacokinetic population model was developed using 639 salbutamol sulphate concentration-time data corresponding to 52 Wistar rats (12  concentrations per animal) divided in 5 groups receiving IV salbutamol sulphate solution either 1 or 3 mg, IP salbutamol sulphate solution either 1 or 3 mg, or salbutamol oral solution at the dose of 16 mg.

Concentration-time profiles were analyzed through non-linear mixed-effects modelled by extended least-squares regression [3], using the first order estimation method (FO). The NONMEM package (Globomax LLC, Hanover, MD, USA)version V level 1.1 was used, with the NM-TRAN version III level 1 and PREDPP version IV level 1.0 [4], installed on a PC Pentium IV platform. Compilation was achieved using the Microsoft Compact Visual Fortran (version 6.5.0). Graphical and other statiscal analyses, including evaluation of NONMEM outputs, were performed using the S-Plus 6.1 Professional. For hierarchical models, the improvement in the fit obtained through the inclusion of a fixed effect into the overall model was assessed using the likelihood ratio test (LRT).

The pharmacokinetic analysis was based on a two compartment kinetic model, with first-order elimination and first order absorption from intestinal lumen to blood. For all models tested, subroutine ADVAN6 and differential equations were used.

Several pharmacokinetics models of different complexities were tried. Models with and without lag time were fitted in order to characterize oral absorption. The possibility of a biphasic oral absorption was also tested.

Results: Complex description of the final pharmacokinetic model selected, statistical analyse and quantitative results will be presented in the poster.

[1] Ahrens, R.C., Smith, G.D., 1984. Albuterol: an adrenergic agent for use in the treatment of asthma pharmacology, pharmacokinetics and clinical use. Pharmacotherapy, 4, 105-121.
[2] Pacifici, G.M., Giulianetti, B., Quilici, M.C., Spisni, R., Nervi, M., Giuliani, L., Gomeni, R., 1997. (-)-salbutamol sulphate sulphation in the human liver and duodenal mucosa: interindividual variability. Xenobiotica, 27, 279-286.
[3] Lindstrom, M.J., Bates, T.M., 1990. Nonlinear mixed effects models for repeated measures. Biometrics, 46, 673-687.
[4] Beal, S.L., Boeckmann, A., Sheiner, L.B., 1988-1998. NONMEM users guides - Part I-VIII, NONMEM Project Group C2555. San Francisco: University of California at San Francisco. 

Reference: PAGE 15 (2006) Abstr 993 [www.page-meeting.org/?abstract=993]
Poster: Applications- Other topics