Medicine, London Health Sciences Centre, London, Ontario, Canada.
Medicine, London Health Sciences Centre, London, Ontario, Canada
BMJ Open. 2020 Mar 4;10(3):e034086. doi: 10.1136/bmjopen-2019-034086.
Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications.
A phase I, open-label, single-dose, pharmacokinetic study.
London, Ontario, Canada.
Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68).
Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice.
Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice.
Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.
乳糜泻的严重程度部分取决于小肠黏膜损伤的程度。病理学最异常的患者会失去十二指肠绒毛 CYP3A4，这是一种药物代谢酶，可使许多药物失活。据推测，这些患者体内的非洛地平（felodipine）系统浓度更高，非洛地平由于肠道 CYP3A4 介导的代谢，通常具有较低的口服生物利用度，属于可代表包含许多药物的一类药物。
一项 I 期、开放标签、单剂量、药代动力学研究。
加拿大安大略省伦敦。
乳糜泻患者（n=47），血清学阳性且健康个体（n=68）。
在 3 周内进行乳糜泻患者上消化道内镜检查和口服非洛地平药代动力学研究。健康个体-口服非洛地平药代动力学研究，分别用水和葡萄柚汁。
乳糜泻分层类别：A 组（n=15，正常），B+C 组（n=16，上皮内淋巴细胞增多症伴/不伴轻度绒毛变钝）和 D 组（n=16，中度/重度绒毛变钝）。A、B+C 和 D 组的非洛地平 AUC 呈线性趋势增加；平均值±SEM，14.4±2.1、17.6±2.8、25.7±5.0；p<0.05）和 Cmax（3.5±0.5、4.0±0.6、6.4±1.1；p<0.02）。接受水的健康受试者的非洛地平 AUC（11.9±0.9 对 26.9±0.9，p=0.0001）和 Cmax（2.9±0.2 对 7.7±0.2，p=0.0001）低于接受葡萄柚汁的健康受试者。
乳糜泻患者非洛地平浓度增加很可能是由于小肠 CYP3A4 表达减少所致。严重乳糜泻患者和健康个体饮用葡萄柚汁后的效果相似增强。因此，严重乳糜泻患者可能会经历类似的药物反应改变，包括来自许多已知由 CYP3A4 代谢的重要药物的过量毒性。患有严重乳糜泻的患者应考虑其他临床药物管理，特别是当存在严重药物毒性的潜在风险时。
