Abstract
Parkinson’s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut.
Highlights
Parkinson’s disease is one of the most common neurodegenerative diseases affecting more than1% of the elderly population [1,2]
Assay performance was determined by assessing the accuracy and precision of Quality control (QC) samples with three different concentrations (15.03, 165.29, and 1818.18 ng/microsome volume (mL))
The observed mean maximum plasma concentration (Cmax ) after oral administration was 6.67 and 58.29 ng/mL and the area under the curve from 0 min to the last measured time point was 1125.53 and 6599.69 ng·min/mL at 1 and 5 mg/kg doses, respectively. These results showed that ZM241385 was rapidly eliminated in rats and the systemic clearance was almost similar to hepatic blood flow (55.2 mL/min/kg)
Summary
1% of the elderly population [1,2] It is characterized by four symptoms such as rigidity, bradykinesia, tremor, and postural instability [3]. As the disease progresses and DA neurons are lost, the efficacy of L-dopa diminishes and motor fluctuation (such as wearing-off and on-off phenomena) and dyskinesia tend to appear in the PD patients [7,8,9] It appears to be at increased risk for non-dopamine-related symptoms such as cognitive and psychiatric dysfunctions become more prominent, leading to long-term disability [10,11,12,13]
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