Abstract
The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software. A detailed sub-model was implemented for kidneys to handle the complex disposition of CMS and colistin within this organ. The WB-PBPK model well captured the kinetic profiles of CMS and colistin in plasma. In kidneys, an accumulation and slow elimination of colistin were observed and well described by the model. Kidneys seemed to have a major role in the elimination processes, through tubular secretion of CMS and intracellular degradation of colistin. Lastly, to illustrate the usefulness of the PBPK model, an estimation of the withdrawal periods after veterinary use of CMS in pigs was made. The WB-PBPK model gives an insight into the renal distribution and elimination of CMS and colistin in pigs; it may be further developed to explore the colistin induced-nephrotoxicity in humans.
Highlights
Colistin is an old peptide antibiotic from the polymyxin family that is used in human and veterinary medicines
Determination is achieved in an indirect way: a separate aliquot of each sample was pre-treated with sulphuric acid at 0.5M to hydrolyse colistimethate sodium (CMS) to colistin and the concentration of CMS was determined by difference between the concentrations measured before and after the acid hydrolysis, accounting for the differences in molecular weights of CMS and colistin
The 419 measurement of colistin concentrations in the buffer samples at 37 °C indicated that less than 6% of 420 CMS was hydrolysed into colistin after 30 min
Summary
Colistin is an old peptide antibiotic from the polymyxin family that is used in human and veterinary medicines. The use of its pro-drug, the colistimethate sodium (CMS), is the most frequent in human medicine but CMS can be found as animal treatment. In many cases colistin has become the last resort antibiotic against multi-resistant bacteria (1). Colistin is the active moiety and is formed from CMS hydrolysis within the body (2). CMS is a mixture of methanesulfonated molecules, which are hydrolysed in colistin by loss of methanesulfonate groups (3). The structures of colistin and CMS are responsible for their complex absorption, distribution, metabolism, and excretion (ADME), which depend on poorly described biological mechanisms (see below). Because of the renewed interest for colistin, clarifying this complexity is essential in order to improve dosing adjustments and to avoid toxic effects (4)
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