A sensitive and fast LC-MS/MS method for determination of β-receptor agonist JP-49b

Application to a pharmacokinetic study in rats

Hui He, Kimberly Williams-Guy, Jayaprakash Pagadala, Chaela Sickbert Presley, Duane Miller, Jena J. Steinle, Charles Yates

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Ocular administration of the beta (β)-adrenergic receptor agonist JP-49b prevents retinopathy-like damage in a preclinical rat model of diabetes. Importantly, JP-49b did not induce characteristic β-adrenergic agonist-related side effects (e.g., left ventricular damage), which led to the hypothesis that JP-49b systemic exposure was minimal following ocular administration. To test this hypothesis, a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to study the preclinical pharmacokinetics of JP-49b in rats. Animals received either a single periocular or intravenous injection of JP-49b (10mg/kg) and plasma and tissue samples were obtained. JP-49b and fenoterol hydrobromide (internal standard, IS) were isolated by liquid-liquid extraction and extracts were analyzed by reversed-phase liquid chromatography on a C18 column using a gradient elution (acetic acid in water and methanol). A triple quadrupole mass spectrometer operating in the positive electrospray ionization mode with multiple reaction monitoring was used to detect JP-49b and IS transitions of m/z 346.4→195.1 and 304.1→134.9. The method was validated for selectivity, linearity, accuracy, and precision in rat vitreous humor, tissue homogenates, and plasma. Following intravenous administration, JP-49b was found to have a rapid clearance (36±5.8L/h/kg), high volume of distribution (244±51.5L/kg) and a terminal half-life of 4.8±1.6h. JP-49b was rapidly absorbed and extensively distributed into ocular tissue following topical administration. However, JP-49b was undetectable in heart tissue 24h after ocular administration. High local drug concentrations coupled with minimal systemic exposure following ocular administration supports further testing of JP-49b as a localized therapy for diabetic retinopathy.

Original languageEnglish (US)
Pages (from-to)86-91
Number of pages6
JournalJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume953-954
Issue number1
DOIs
StatePublished - Mar 15 2014

Fingerprint

Pharmacokinetics
Rats
Ophthalmic Administration
Tissue
Liquid chromatography
JP-49b
Intraocular Injections
Fenoterol
Plasmas
Topical Administration
Vitreous Body
Electrospray ionization
Adrenergic beta-Agonists
Adrenergic Agonists
Liquid-Liquid Extraction
Liquids
Mass spectrometers
Diabetic Retinopathy
Reverse-Phase Chromatography
Medical problems

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Analytical Chemistry
  • Cell Biology
  • Clinical Biochemistry

Cite this

A sensitive and fast LC-MS/MS method for determination of β-receptor agonist JP-49b : Application to a pharmacokinetic study in rats. / He, Hui; Williams-Guy, Kimberly; Pagadala, Jayaprakash; Presley, Chaela Sickbert; Miller, Duane; Steinle, Jena J.; Yates, Charles.

In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, Vol. 953-954, No. 1, 15.03.2014, p. 86-91.

Research output: Contribution to journalArticle

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