Abstract
PMX53 and PMX205 are cyclic hexapeptide inhibitors of complement C5a receptors (C5aR1), that are widely used to study C5aR1 pathobiology in mouse models of disease. Despite their widespread use, limited information regarding their pharmacokinetics have been reported. Here, a bioanalytical method for the quantitative determination of PMX53 and PMX205 in plasma, brain and spinal cord of mice was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. The LC-MS/MS method was validated in all three matrices according to regulatory guidelines and successfully applied to pharmacokinetic studies of PMX53 and PMX205 in C57BL/6 J mice following intravenous administration. The developed method was highly sensitive and sufficiently accurate with a lower limit of quantification within the range of 3–6 ng/ml in extracted plasma samples and 3–6 ng/g in processed tissue samples, which outperforms previously published LC-MS/MS methods. The results thus support the suitability, reliability, reproducibility and sensitivity of this validated technique. This method can therefore be applied to perform a complete pre-clinical investigation of PMX53 and PMX205 pharmacokinetics in mice.
Highlights
An enzymatic cascade, the complement system is a vital component of the immune system creating a bridge between the innate and adaptive immune systems
PMX205 is a lipophilic analogue of PMX53 that demonstrates improved in vivo stability and efficacy[5,15,16], and has been suggested as a more ideal drug candidate, for neurological diseases
The mass spectrometer was operated in multiple reaction monitoring (MRM) scan mode for identification of an ideal ionization state for fragmentation
Summary
The complement system is a vital component of the immune system creating a bridge between the innate and adaptive immune systems. PMX205 is a lipophilic analogue of PMX53 that demonstrates improved in vivo stability and efficacy[5,15,16], and has been suggested as a more ideal drug candidate, for neurological diseases This drug has shown beneficial effects in models of Huntington’s disease[5], amyotrophic lateral sclerosis[4,16], spinal cord injury[6,17], and in reduction of memory loss in mice with Alzheimer’s disease[18,19]. Experimental inflammatory conditions for over 15 years, and oral and topical PMX53 has been tested in early Phase I human clinical trials[20] Despite this extensive usage of these C5aR1 inhibitors, relatively few studies have reported the quantitative pharmacokinetic determination of these antagonists[7,13,15,21,22]. This method was successfully utilised for pharmacokinetic studies of PMX53 and PMX205 in mice following the intravenous (i.v.) route of administration, and may be useful for determining the complete comparative preclinical pharmacokinetics of these drugs in mice
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