Bioavailability of Paracetamol, Amoxicillin and Talinolol and Expression of Intestinal Drug Metabolizing Enzymes and Transport Proteins Before, Immediately and One Year After Proximal Roux-en-Y Gastric Bypass Operation in Patients With Morbid Adipositas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- area under the concentration time curve of paracetamol, amoxicillin and talinolol
研究概览
简要总结
The purpose of this study is to evaluate pharmacokinetics of paracetamol, amoxicillin and talinolol in morbid adipose subjects before as well as shortly after and about one year after proximal Roux-en-Y Gastric Bypass (RYGB) and to measure messenger ribonucleic acid (mRNA) expression and protein content of duodenal and/or jejunal drug metabolizing enzymes (eg. cytochrome P450 isoenzyme 3A4 (CYP3A4), uridine diphosphoglucuronosyltransferase (UGTs)) and drug transport proteins (e.g. P-glycoprotein, MRP2, OATPB, PEPT) before and during the operation and about one year after proximal RYGB.
详细描述
Intestinal drug absorption appears to be a very complex process characterized by gastrointestinal transit, disintegration of dosage forms, drug dissolution within the intestinal lumen, active and passive uptake processes, mucosal metabolism (e.g. by cytochrome P450 (CYP), UGT, sulfotransferase (SULT) enzymes) and efflux transport by several adenosine triphosphate binding cassette (ABC) transporters as P-glycoprotein, multidrug resistance associated protein (MRP) 2 or breast cancer resistance protein (BCRP). Along the gastrointestinal tract, the upper small intestine (i.e. duodenum, proximal jejunum) represents the main site for absorption of nutrients and drugs offering an appropriately large absorption area of nearly 200 m². Within this bowel segment, there is a high expression of several physiological relevant uptake carriers for nutrients as carbohydrates (e.g. GLUTs), fatty acids (MCTs, FATs), peptides (PEPTs), sterols (NPC1L1) and bile acids (ASBT) which are exclusively located in the small intestine. Furthermore, it is now well established that there is a high intestinal expression of phase I & II metabolizing enzymes as well as drug efflux transporters being responsible for the high first-pass metabolism of many compounds like cyclosporine, nifedipine, midazolam or statins. Apparently, there is a distinct expression gradient along the small intestine (e.g. decreasing levels of P-gp and CYP3A4 but increasing for MRP2). On the other side, the colon features only negligible amounts of enzymes and active uptake and elimination carriers. Therefore, the extent of drug absorption from the bowel is mainly dependent on the intestinal site of drug liberation and, thus, dependent on the administered dosage form, the physicochemical properties of the drug and the individual physiological conditions.
Due to the fact, that under physiological circumstances there is only a low expression of P-gp in the upper parts of the gut (i.e. duodenum and jejunum), a functional "absorption window" is created which enables the preferable absorption of drugs in these proximal region of the small intestine. This is also supported by the markedly higher surface area of the upper small intestine compared to distal segments. It was shown that cyclosporine and talinolol were increasingly less absorbed when delivered into deeper regions of the human intestine. Since both compounds are well established P-gp substrates, this site-dependent absorption phenomenon seems to be caused by the decreasing expression levels of intestinal P-gp counteracting drug uptake into enterocytes. Additionally, it was reported that the effective permeability of atenolol, metoprolol, cimetidine and furosemide was markedly lower in the ileum compared to the jejunum in healthy subjects. These data verified that drug absorption in the lower intestine is less effective than in upper parts which seems to be of outstanding relevance for compounds with predominately duodenal and jejunal absorption (fast release dosage form) and P-gp substrates as ß-lactam antibiotics, furosemide, cyclosporine, talinolol and digoxin.
Consequently, in subjects after massive dissection of the proximal small intestine or after Roux-en-Y gastric bypass surgery, absence of this main intestinal absorption area leads to malabsorption of nutrients (e.g. protein, fat soluble vitamins, minerals and trace elements as iron) and is expected to affect the oral bioavailability of drugs with "absorption window" in the proximal small intestine.
Roux-en-Y gastric bypass surgery, by which the stomach, the duodenum and parts of the jejunum are dislocated from the continuous intestinal passage of the chyme, is the surgical gold standard option to treat morbid adipositas. The method was shown to reduce significantly body weight and obesity-related co-morbidity. Today, this surgical intervention is the most frequently used bariatric surgery (USA: approximately 150.000/year) and its application is still increasing.
Despite its widely use and the well documented risk of nutrient deficiencies, only very little is known about the pharmacokinetic consequences and intestinal adaptation mechanisms in these patients who are often subjected to multiple drug therapy. It was assumed that the reduced intestinal surface area and the reduced time to drug disintegration and dissolution caused by accelerated intestinal transit in these patients are associated with lowered intestinal drug absorption. Additionally, this could be affected by the reduced production of gastric hydrochloric acid by lowering the solubility in case of alkaline drugs. However, it is possible that compensatory processes by other bowel segments could improve drug absorption which could mean that drugs are still adequately absorbed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •patients who are subjected to proximal stomach-bypass surgery by entire medical reasons independent of the objectives of this study
- •age: over 18 years
- •sex: male and female
- •ethnic origin: Caucasian
- •written informed consent
排除标准
- •abnormal low hemoglobin values (< 6.5 mmol/l [female]; < 7.6 mmol/l [male])
- •obstructive lung disease (e.g. bronchial asthma)
- •acute myocardial infarction
- •peripheral arterial circulatory disturbance
- •any disturbance of impulse formation and conduction
- •bradycardia (< 50 beats/min)
- •hypotension (systolic pressure < 90 mmHg)
- •phaeochromocytoma
- •subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to as a result of their participation in the study
- •blood donation or other blood loss of more than 400 ml within the last 3 months prior to the start of the study
- •participation in a clinical trial during the last 3 months prior to the start of the study
- •less than 14 days after last acute disease
- •treatment with paracetamol, amoxicillin or talinolol 7 days before the study
- •repeated use of drugs during the last 4 weeks prior to the intended first administration, which can influence drug biotransformation and drug transport
- •intake of grapefruit containing food or beverages within 7 days prior to administration
- •known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparation, also against penicillin
- •subjects with severe allergies or multiple drug allergies
研究组 & 干预措施
pre OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed within three days before the scheduled proximal Roux-en-Y gastric bypass surgery. A gastroduodenoscopy with biopsy of the lower duodenum will be performed before the first pharmacokinetic study period.
干预措施: paracetamol (Drug)
pre OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed within three days before the scheduled proximal Roux-en-Y gastric bypass surgery. A gastroduodenoscopy with biopsy of the lower duodenum will be performed before the first pharmacokinetic study period.
干预措施: amoxicillin (Drug)
pre OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed within three days before the scheduled proximal Roux-en-Y gastric bypass surgery. A gastroduodenoscopy with biopsy of the lower duodenum will be performed before the first pharmacokinetic study period.
干预措施: talinolol (Drug)
pre OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed within three days before the scheduled proximal Roux-en-Y gastric bypass surgery. A gastroduodenoscopy with biopsy of the lower duodenum will be performed before the first pharmacokinetic study period.
干预措施: gastroduodenoscopy with biopsy (Procedure)
post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed 5-7 days after the scheduled proximal Roux-en-Y gastric bypass surgery. A sampling of a tissue specimen from the jejunum will be collected during the operation.
干预措施: paracetamol (Drug)
post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed 5-7 days after the scheduled proximal Roux-en-Y gastric bypass surgery. A sampling of a tissue specimen from the jejunum will be collected during the operation.
干预措施: amoxicillin (Drug)
post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed 5-7 days after the scheduled proximal Roux-en-Y gastric bypass surgery. A sampling of a tissue specimen from the jejunum will be collected during the operation.
干预措施: talinolol (Drug)
post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed 5-7 days after the scheduled proximal Roux-en-Y gastric bypass surgery. A sampling of a tissue specimen from the jejunum will be collected during the operation.
干预措施: proximal Roux-en-Y gastric bypass (Procedure)
one year post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period and a gastrojejunoscopy with biopsy of the jejunum will be performed about one year after the scheduled proximal stomach bypass surgery.
干预措施: paracetamol (Drug)
one year post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period and a gastrojejunoscopy with biopsy of the jejunum will be performed about one year after the scheduled proximal stomach bypass surgery.
干预措施: amoxicillin (Drug)
one year post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period and a gastrojejunoscopy with biopsy of the jejunum will be performed about one year after the scheduled proximal stomach bypass surgery.
干预措施: talinolol (Drug)
one year post OP
The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period and a gastrojejunoscopy with biopsy of the jejunum will be performed about one year after the scheduled proximal stomach bypass surgery.
干预措施: gastrojejunoscopy with biopsy (Procedure)
结局指标
主要结局
area under the concentration time curve of paracetamol, amoxicillin and talinolol
时间窗: up to 1.5 h before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 h after study medication
次要结局
- maximal concentration of the concentration time curve of paracetamol, amoxicillin and talinolol(up to 1.5 h before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 h after study medication)
- timepoint of the maximal concentration of the concentration time curve of paracetamol, amoxicillin and talinolol(up to 1.5 h before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 h after study medication)
- terminal half-life of the concentration time curve of paracetamol, amoxicillin and talinolol(up to 1.5 h before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 h after study medication)
- mRNA expression determined by quantitative polymerase chain reaction given as cycle threshold normalized to house keeping gene 18S and villin(up to 2 days before the first study medication and after at least 6 h fasting, during proximal Roux-en-Y gastric bypass surgery within 3 days after first study medication and about one year after proximal Roux-en-Y gastric bypass surgery)
- protein abundance determined by liquid chromatography-mass spectrometry based targeting proteomics normalized to villin(up to 2 days before the first study medication and after at least 6 h fasting, during proximal Roux-en-Y gastric bypass surgery within 3 days after first study medication and about one year after proximal Roux-en-Y gastric bypass surgery)