Novel protocol for multiple-dose oral administration of the L-type Ca ²⁺ channel blocker isradipine in mice: A dose-finding pharmacokinetic study

Abstract

Studies in genetically modified animals and human genetics have recently provided new insight into the role of voltage-gated L-type Ca 2+ channels in human disease. Therefore, the inhibition of L-type Ca 2+ channels in vivo in wildtype and mutant mice by potent dihydropyridine (DHP) Ca 2+ channel blockers serves as an important pharmacological tool. These drugs have a short plasma half-life in humans and especially in rodents and show high first-pass metabolism upon oral application. In the vast majority of in vivo studies, they have therefore been delivered through parenteral routes, mostly subcutaneously or intraperitoneally. High peak plasma concentrations of DHPs cause side effects, evident as DHP-induced aversive behaviors confounding the interpretation of behavioral readouts. Nevertheless, pharmacokinetic data measuring the exposure achieved with these applications are sparse. Moreover, parenteral injections require animal handling and can be associated with pain, discomfort and stress which could influence a variety of physiological processes, behavioral and other functional readouts. Here, we describe a noninvasive oral application of the DHP isradipine by training mice to quickly consume small volumes of flavored yogurt that can serve as drug vehicle. This procedure does not require animal handling, allows repeated drug application over several days and reproducibly achieves peak plasma concentrations over a wide range previously shown to be well-tolerated in humans. This protocol should facilitate ongoing nonclinical studies in mice exploring new indications for DHP Ca 2+ channel blockers.

Natural L-type calcium channels antagonists from Chinese medicine

“…Furthermore, the LTCCs were new promising targets for many diseases, such as drug-addiction [ 33 , 34 ], depressive disorder [ 109 ], age-related macular degeneration-retinal pigment epithelium (AMD-RPE) [ 110 ], intrauterine growth restriction [ 111 ], local infiltration analgesia [ 112 ], myalgia [ 113 ], which expanded the scope of application. In addition, calcium channel blocker (CCB) have a short plasma half-life especially in rodents and show high first-pass metabolism upon oral application [ 114 ]. The dosage of CCB should be tightly noticed as the CCBs lose specificity for their specific receptors and can show all the manifestations of toxicity such as bradycardia, peripheral vasodilation, and hypotension in high concentrations [ 115 ].…”