ABSTRACT
Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers.
Subject(s)
Adenosine/analogs & derivatives , Cytochrome P-450 CYP3A/genetics , Liver-Specific Organic Anion Transporter 1/genetics , Platelet Aggregation Inhibitors , Purinergic P2 Receptor Antagonists , Adenosine/blood , Adenosine/pharmacokinetics , Adenosine/pharmacology , Area Under Curve , Asian People/genetics , Genotype , Healthy Volunteers , Humans , Male , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Polymorphism, Single Nucleotide , Purinergic P2 Receptor Antagonists/blood , Purinergic P2 Receptor Antagonists/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacology , TicagrelorABSTRACT
PURPOSE: Bioavailability of clopidogrel in the form of crushed tablets administered via nasogastric tube (NGT) has not been established in patients after cardiopulmonary resuscitation. Therefore, we performed a study comparing pharmacokinetic and pharmacodynamic response to high loading dose of clopidogrel in critically ill patients after cardiopulmonary resuscitation (CPR) with patients scheduled for elective coronary angiography with stent implantation. METHODS: In the NGT group (nine patients, after cardiopulmonary resuscitation, mechanically ventilated, therapeutic hypothermia), clopidogrel was administered in the form of crushed tablets via NGT. Ten patients undergoing elective coronary artery stenting took clopidogrel per os (po) in the form of intact tablets. Pharmacokinetics of clopidogrel was measured with high-performance liquid chromatography (HPLC) before and at 0.5, 1, 6, 12, 24 h after administration of a loading dose of 600 mg. In five patients in each group, antiplatelet effect was measured with thrombelastography (TEG; Platelet Mapping) before and 24 h after administration. RESULTS: The carboxylic acid metabolite of clopidogrel was detected in all patients in the po group. In eight patients, the maximum concentration was measured in the range of 0.5-1 h after the initial dose. In four patients in the of NGT group, the carboxylic acid metabolite of clopidogrel was undetectable and in the remaining patients was significantly delayed (peak values at 12 h). All patients in the po group reached clinically relevant (>50 %) inhibition of thrombocyte adenosine diphosphate (ADP) receptor after 24 h compared with only two in the NGT group (p = 0.012). There was a close correlation between peak of inactive clopidogrel metabolite plasmatic concentration and inhibition of the ADP receptor (r = 0.79; p < 0.001). CONCLUSION: The bioavailability of clopidogrel in critically ill patients after cardiopulmonary resuscitation is significantly impaired compared with stable patients. Therefore, other drugs, preferentially administered intravenously, should be considered.
Subject(s)
Blood Platelets/drug effects , Cardiopulmonary Resuscitation , Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacokinetics , Ticlopidine/analogs & derivatives , Administration, Oral , Aged , Aged, 80 and over , Biological Availability , Blood Platelets/metabolism , Chromatography, High Pressure Liquid , Clopidogrel , Critical Illness , Female , Humans , Hypothermia, Induced , Intubation, Gastrointestinal , Male , Middle Aged , Percutaneous Coronary Intervention/instrumentation , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/blood , Purinergic P2 Receptor Antagonists/administration & dosage , Purinergic P2 Receptor Antagonists/blood , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2/metabolism , Respiration, Artificial , Stents , Tablets , Thrombelastography , Ticlopidine/administration & dosage , Ticlopidine/blood , Ticlopidine/pharmacokineticsABSTRACT
During exercise, sympathetic nervous system activity increases and this contributes to an increase in blood pressure (i.e. exercise pressor reflex). Although animal studies suggest that purinergic P2 receptors on thin fibre sensory nerves are stimulated and evoke this reflex, human data are lacking. In this study, young healthy volunteers performed fatiguing isometric handgrip before and after a local infusion of pyridoxine (i.e. vitamin B(6)) into the 'isolated' circulation of the human forearm. Pyridoxine is converted into a P2-purinoceptor antagonist. Muscle sympathetic nerve activity and blood pressure responses to fatiguing handgrip and post-exercise circulatory occlusion were significantly less after pyridoxine than they were before. These effects were not observed after infusion of saline. These data suggest that P2 receptors contribute to the exercise pressor reflex in humans.