Novel noninvasive assessment of cytochrome P450 activity

细胞色素 P450 活性的新型无创评估

• 批准号: 7600437
• 负责人: Evan D. Kharasch
• 金额: $ 29.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600437
• 关键词: Alfentanil; Blood flow; Breath Tests; CYP3A4 gene; CYP3A5 gene; Caliber; Clinical; Clinical Research; Clinical assessments; Cytochrome P450; Cytochrome a; Cytochromes; Development; Diet; Dose; Drug Interactions; Drug Kinetics; Environment; Enzymes; Erythromycin; Evaluation; Exhibits; Family; Genetic; Genetic Polymorphism; Goals; Hepatic; Human; Hydrocortisone; Ideal 1; In Vitro; Individual; Intestines; Intravenous; Investigation; Kidney Transplantation; Kinetics; Liver; Measures; Meiosis; Metabolism; Midazolam; Opioid; Oral; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Population; Predisposition; Protein Isoforms; Pupil; Reaction; Regulation; Reproducibility; Research; Sampling; Substrate Specificity; Tacrolimus; Technology; Testing; Therapeutic; Therapeutic Index; Time; Transplant Recipients; Treatment outcome; Urine; Validation; base; clinically significant; comparative; constriction; cost; dosage; drug candidate; drug development; drug metabolism; healthy volunteer; in vivo; inhibitor/antagonist; minimally invasive; new technology; novel; programs; quantum; response; stable isotope; success

DESCRIPTION (provided by applicant): Cytochrome P450s of the 3A family (CYP3A) are perhaps the most clinically significant human drug metabolizing enzymes CYP3A4 is the most abundant hepatic and intestinal CYP. CYP3A5 metabolizes many, but not all, CYP3A4 substrates CYP3As metabolize >50% of all drugs, are a major determinant of first-pass (intestinal and hepatic) metabolism of oral drugs, and exhibit marked inter-individual variability due to diverse CYP3A4 expression, CYP3A5 genetic polymorphism and exquisite CYP3 A sensitivity to drug interactions. A major imperative has been the assessment of CYP3A activity, drug interactions, and resulting alterations in clinical drug effects. FDA regulations regarding new drug development require the identification of metabolizing enzyme(s) and clinical assessment of potential pharmacokinetic drug interactions. Myriad endeavors to identify and validate an ideal in vivo CYP3A probe have, unfortunately, not succeeded. All current CYP3A probes have known limitations, require some invasiveness, and are based on plasma or urine pharmacokinetics. The goal of this research program is to develop and implement a simple, sensitive, specific, inexpensive, and robust probe for the minimally or noninvasive assessment of CYP3A activity and drug interactions in humans. This investigation will test the hypothesis that the CYP3A opioid substrate alfentanil (ALF) can be used to minimally or non-invasively assess CYP3A activity. Specifically, that hepatic and first-pass CYP3A can be 1) simultaneously assessed in a single session and with a single minimal plasma sample using stable isotope ALF, and 2) individually assessed using pupil constriction (miosis) as a totally noninvasive surrogate for ALF plasma concentration and pharmacokinetics. That is, "effect clearance" can replace plasma clearance, and thus ALF miosis is a noninvasive in vivo probe for CYP3A. Clinical studies in healthy volunteers and patients, using midazolam clearance as an independent measure of CYP3A, will evaluate relationships between ALF single-point concentration (minimally invasive probe), ALF effect clearance (noninvasive probe), ALF plasma clearance and CYP3A activity, for intravenous and oral ALF, to determine the: 1) validity of simultaneous hepatic and first-pass CYP3A single-point assessment, 2) probe sensitivity for detecting graded CYP3A induction, 3) influence of hepatic blood flow on the clearance of the CYP3A probes midazolam and ALF, and 4) ability of noninvasive ALF miosis to predict dose requirements for other CYP3A drugs. Successful validation and implementation of ALF will provide a novel technology for assessing CYP3A, the most important drug metabolism enzyme. This approach may identify inter-individual variability in drug disposition and response; permit more individualized dosing, and reduces the cost of drug interaction studies.

描述（由申请人提供）：3A家族（CYP3A）的细胞色素P450可能是临床上最重要的人类药物代谢酶CYP3A4是最丰富的肝和肠道CYP。 CYP3A5 metabolizes many, but not all, CYP3A4 substrates CYP3As metabolize >50% of all drugs, are a major determinant of first-pass (intestinal and hepatic) metabolism of oral drugs, and exhibit marked inter-individual variability due to diverse CYP3A4 expression, CYP3A5 genetic polymorphism and exquisite CYP3 A sensitivity to drug互动。主要的当务之急是评估CYP3A活性，药物相互作用以及临床药物作用的改变。关于新药物开发的FDA法规需要鉴定代谢酶和潜在的药代动力学相互作用的临床评估。不幸的是，无数努力以识别和验证体内CYP3A探针的理想选择。当前所有CYP3A探针都有已知的局限性，需要一些侵入性，并且基于血浆或尿液药代动力学。该研究计划的目的是开发和实施对人类CYP3A活性和药物相互作用的最小或无创评估的简单，敏感，廉价且健壮的探测器。这项研究将检验以下假设：CYP3A阿片底物Alfentanil（ALF）可用于微小或非侵入性评估CYP3A活性。具体而言，肝和第一频繁的CYP3A可以为1）在一次会话中同时评估，并使用稳定的同位素ALF进行单个最小的血浆样品，以及2）使用学生收缩（Miosis）单独评估，作为ALF血浆浓度和药物运动的完全无侵蚀性替代物。也就是说，“效应清除率”可以替代血浆清除率，因此Alf Miosis是CYP3A的体内探针无创。使用咪达唑仑清除率作为CYP3A的独立度量，在健康志愿者和患者中的临床研究将评估ALF单点浓度（微创探针）之间的关系，ALF效应清除率（非侵入性探针），ALF血浆清除率和CYP3A活性，以确定静脉和口腔ALF，以确定静脉和口头效率：单点评估，2）用于检测分级CYP3A诱导的探针灵敏度，3）肝血流对CYP3A探针脱唑仑和ALF清除的影响，以及4）非侵入性ALF MIOSIS预测其他CYP3A药物的剂量需求的能力。 ALF的成功验证和实施将为评估CYP3A（最重要的药物代谢酶）提供新的技术。这种方法可以识别药物处置和反应的个体间变异性；允许更多个性化的剂量，并降低药物相互作用研究的成本。

项目成果

Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.

细胞色素 P4503A 不介导美沙酮和利托那韦-洛匹那韦之间的相互作用。

• DOI: 10.1124/dmd.113.053991
• 发表时间: 2013
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: Kharasch,EvanD;Stubbert,Kristi
• 通讯作者: Stubbert,Kristi

Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update.

• DOI: 10.1002/cpt.597
• 发表时间: 2017-07
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Hicks JK;Sangkuhl K;Swen JJ;Ellingrod VL;Müller DJ;Shimoda K;Bishop JR;Kharasch ED;Skaar TC;Gaedigk A;Dunnenberger HM;Klein TE;Caudle KE;Stingl JC
• 通讯作者: Stingl JC