Pharmacokinetic properties of isradipine after single‐dose and multiple‐dose oral administration in Chinese volunteers: a randomized, open‐label, parallel‐group phase I study

Abstract

Isradipine could be used for the treatment of high blood pressure or Parkinsonism, yet the study on pharmacokinetics (PK) of isradipine is lacking in the Chinese population. The current study aims to assess the dose proportionality, pharmacokinetics and gender effect of isradipine following oral single and multiple doses in Chinese subjects. A randomized, open-label, parallel-group trial was conducted in 30 healthy Chinese volunteers. Subjects randomly received a single dose of 2.5, 5 or 10 mg, and multiple doses (2.5 mg) of isradipine. Blood samples were collected pre-dose (0 h) and 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36 and 48 h post-dose. Isradipine was rapidly absorbed with the time to maximum concentration <1.27 h for all dosage groups. The maximum concentrations were 2.46, 5.34, 10.93 and 3.32 ng/mL and area under the concentration-time curve from time zero to the last time point (AUClast ) were 7.05, 12.58, 24.68 and 5.31 ng/ml · h for the 2.5, 5 and 10 mg single-dose and 2.5 mg multiple-dose groups, respectively. The half-life ranged from 5.76 to 7.94 h. The maximum concentration and AUC were found to increase linearly and dose-dependently for isradipine. No statistical gender differences were found. These findings indicated that the pharmacokinetic parameters of isradipine in Chinese population were dose-proportional and predictable over a range of 2.5-10 mg isradipine oral doses.

Lower Affinity of Isradipine for L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease

“…Together with Ca v 1.2, we also detected robust expression of Ca v 1.3. Ca v 1.3 L was the predominantly expressed splice variant, but the most abundant short splice variants in the brain, Ca v 1.3 43S and Ca v 1.3 42A Tan et al, 2011), were also expressed in SN DA neurons (Fig. 2C).…”

“…Pumps were loaded with ISR dissolved in vehicle [dimethylsulfoxide (DMSO)/ PEG300]. Neuroprotective effects of ISR were assessed only in mice in which plasma concentrations of ISR Ͼ3 ng/ml were reached that correspond to human therapeutic steady-state plasma levels [Christensen et al, 2000;Park et al, 2009;Wang et al, 2013; SPC Lomir (compendium.ch/mpro/mnr/ 2604/html/)]. ISR mouse plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.…”

“…Neurons in the SN were visualized with a fixed-stage upright microscope (model BX51WI, Olympus) using a 20ϫ water-immersion objective (0.95 numerical aperture; 2 mm working distance; XLUMPLFL, Olympus) with a 4ϫ magnification changer (U-TVAC, Olympus), infrared differential interference contrast optics (Dodt and Zieglgänsberger, 1994), and fluorescence optics. Ventral tier SN DA neurons were identified by the size and location of their somata, by electrophysiological fingerprints, and by post hoc immunohistochemistry for TH (Lacey et al, 1989;Richards et al, 1997;Ungless et al, 2001). Biocytin-streptavidin labeling combined with TH immunohistochemistry was performed as previously described (Hess et al, 2013).…”

“…L-type voltage-gated Ca 2ϩ channels [LTCCs (Ca v 1); Catterall et al, 2005] are required for normal endocrine, brain, sensory, and muscle function , and brain Ca v 1.2 and Ca v 1.3 channels are also expressed by SN DA neurons (Olson et al, 2005;Dragicevic et al, 2014;Philippart et al, 2016;Sun et al, 2017). Ca v 1.3 channels can open at subthreshold membrane potentials due to their negative activation voltage range (Koschak et al, 2001;Xu and Lipscombe, 2001;Lieb et al, 2014) and are thus postulated to be a major contributor to mitochondrial stress-inducing Ca 2ϩ oscillations in SN DA neurons Hurley and Dexter, 2012;Hurley et al, 2013;Sulzer and Surmeier, 2013;Branch et al, 2014).…”

“…DHP channel blockers are nonselective, blocking both Ca v 1.2 and Ca v 1.3 channels (Koschak et al, 2001;Xu and Lipscombe, 2001). Ca v 1.3-selective blockers would avoid Ca v 1.2-mediated cardiovascular side effects but are unestablished (Kang et al, 2012;Huang et al, 2014;Ortner et al, 2014). Although human epidemiological studies indicate a 20 -30% lower risk of the development of PD in patients treated with nonselective brain-permeant DHP channel blockers for references), preclinical in vivo studies with DHP channel blockers in PD animal models are controversial.…”