Pharmacokinetic study of the novel phosphocholine derivative 3-dibutylaminopropylphosphonic acid by LC-MS coupling

J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Dec 1;1186:122998. doi: 10.1016/j.jchromb.2021.122998. Epub 2021 Nov 8.

Abstract

CRP is an important mediator of the inflammatory response. Pro-inflammatory CRP effects are mediated by pCRP* and mCRP, dissociation products of the native pCRP. The concentration of pCRP during inflammation may rise up to concentrations 1000-fold from baseline. By prevention of the conformational change from pCRP to pCRP*, pro-inflammatory immune responses can be inhibited and local tissue damage reduced. 3-(Dibutylamino)propylphosphonic acid (C10m) is a new substance that can suppress ischemic-reperfusion injury by targeting CRP in the complement cascade. It hampers dissociation of pCRP into its monomers, thus preventing exacerbation of tissue inflammation subsequent to reperfusion injury. In this study, the pharmacokinetics and metabolism of the new drug candidate C10m was investigated. A sensitive and selective method for detection of C10m and its metabolites from plasma and urine was developed with LC-MS and LC-MS/MS coupling. The LLOQ is at 0.1 µg mL-1 and recovery at 87.4% ± 2.8%. Accuracy and precision were within 15% coefficient of variation and nominal concentrations, respectively. Concentration time profile after i.v. bolus injection of C10m was analyzed by LC-MS/MS. Bioavailability has shown to be below 30%. Most likely due to the compounds' very polar chemical properties, no phase-I or phase-II metabolism could be observed. Absence of phase-I metabolism was cross-checked by performing microsomal incubations. Our study revealed that C10m is rapidly eliminated via urine excretion and that half-times appear to be increased with coadministration of the target pCRP.

Keywords: LC-MS; Pharmacokinetic study; Quantification; Reperfusion injury; Validation; pCRP.

Publication types

  • Evaluation Study

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / blood
  • Anti-Inflammatory Agents / pharmacokinetics*
  • Anti-Inflammatory Agents / urine
  • Chromatography, Liquid / methods*
  • Complement System Proteins / immunology
  • Humans
  • Mass Spectrometry
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / immunology
  • Phosphorylcholine / blood
  • Phosphorylcholine / pharmacokinetics*
  • Phosphorylcholine / urine
  • Rats
  • Tandem Mass Spectrometry / methods*

Substances

  • Anti-Inflammatory Agents
  • Phosphorylcholine
  • Complement System Proteins