Pantoprazole: from drug metabolism to clinical relevance

BACKGROUND: Conditions requiring inhibition of acid secretion, such as gastro-oesophageal reflux disease (GORD), peptic ulcers, non-ulcer dyspepsia or the use of NSAIDs, are very common, and their prevalence is expecting to rise as they are seen predominantly amongst the elderly. Among the drugs available to inhibit acid secretion, proton pump inhibitors (PPI) have been shown to have the best efficacy-safety ratio and have been used widely. OBJECTIVE: This paper was intended to provide an overall presentation of one of these PPIs, pantoprazole. METHOD: This study was first intended to give an overview of pantoprazole, so a Medline search was conducted using pantoprazole as unique search term, without publication date restriction. We found 826 references for pantoprazole and selected some of the most relevant publications to conduct this review. RESULTS/CONCLUSION: Five different PPIs are commercially available: omeprazole, pantoprazole, rabeprazole, lansoprazole and esomeprazole. Pantoprazole differs from other PPIs by a selective binding to the ion transport pathway, a good stability at neutral pH values, and a relatively robust plasma concentration-time curve. These pharmacokinetic differences may not be fully converted into pharmacodynamic differences of pantoprazole versus other PPIs. Pantoprazole has been assessed in most of the clinical situations where acid suppression is required, and showed great efficacy and an excellent safety profile. Some safety concerns were raised with long-term use of PPIs, but they are well balanced by the benefit of PPIs for patients with conditions such as GORD or peptic ulcer.     

Angiotensin II-receptor blockers: clinical relevance and therapeutic role.

The limitations of angiotensin-converting-enzyme (ACE) inhibitors and the role of angiotensin II-receptor blockers (ARBs) in the treatment of hypertension, heart failure, and diabetic nephropathy are discussed. Although ACE inhibitors are generally well tolerated, two important class-related adverse effects are cough, which is common, and angioedema, which is rare but serious. Cough and angioedema appear to be less frequent with ARBs than with ACE inhibitors. ARBs seem to be as capable as ACE inhibitors of producing renal dysfunction. ARBs may offer more complete inhibition of angiotensin II than ACE inhibitors. The mechanism of action is based on selective binding to angiotensin type 1 receptors. Many clinical studies have shown that ARBs lower blood pressure as effectively as other antihypertensive agents, including ACE inhibitors. ARBs do not appear to have a greater clinical effect than ACE inhibitors in patients with heart failure. Some studies of combination ARB and ACE inhibitor therapy for heart failure indicate advantages of the combination over therapy with either class. ARBs may exert renal protective effects in diabetic nephropathy. ARBs offer an alternative to ACE inhibitors in the management of hypertension, especially for ACE-inhibitor-intolerant patients. ACE inhibitors remain the drugs of choice for patients with heart failure, left ventricular dysfunction after MI, and diabetic nephropathy; ARBs offer these patients an alternative when ACE inhibitor therapy is not tolerated.     

Homocysteine levels in patients with stroke: clinical relevance and therapeutic implications

High plasma levels of the amino acid homocysteine have been implicated in the development of vascular diseases, including stroke. Elevated plasma levels of total homocysteine (tHcy) above 15 micromol/L are present in less than 5% of the general population, but in as many as 50% of patients with stroke (and other atherothromboembolic vascular diseases). However, it remains uncertain whether a high tHcy level is a causal risk factor for stroke and should be lowered, or is a marker of another factor associated with stroke (e.g. acute tissue damage or tissue repair after an acute vascular event) and therefore should not be lowered. Plasma levels of tHcy can be lowered effectively by folic acid, vitamin B(6) and vitamin B(12) supplementation, and controlled trials have shown some beneficial effects on surrogate markers of vascular function. However, these markers are not established vascular risk factors or valid predictors of 'hard' clinical vascular outcome events. Until it has been shown in large randomised trials [such as the ongoing Vitamins to Prevent Stroke Study (VITATOPS) and the Vitamins in Stroke Prevention (VISP) study] that multivitamin therapy reduces the rate of recurrent stroke and other serious vascular events in patients with prior stroke or transient ischaemic attack, widespread screening for, and treatment of, high tHcy levels remains experimental and cannot be recommended.     

Neonatal hepatic drug elimination

After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.     

Effects of the antifungal agents on oxidative drug metabolism: clinical relevance

This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.     

Active drug metabolites. An overview of their relevance in clinical pharmacokinetics

This review underlines the importance of considering in the overall evaluation of drug effect and efficacy not only the kinetics and activities of the administered drug, but also those of the chemical species (metabolites) which are formed in the body. The circumstances in which a role for active drug metabolites may be suspected are described, and a number of specific examples are given. Four different categories are described: drugs which are inactive precursors of active metabolites (e.g. DOPA and cyclophosphamide); active metabolites which contribute to the duration of action of the parent compound (e.g. hexamethylmelamine and clobazam); active metabolites showing a mechanism of action different from that of the parent compound (e.g. buspirone and 1-pyrimidinyl piperazine; fenfluramine and norfenfluramine); and active metabolites showing an antagonistic effect on the activity of the parent drug (e.g. trazodone and m-chlorophenyl-piperazine; aspirin and salicylate).     

地高辛血药浓度监测结果与临床疗效分析

目的探讨心衰患者的地高辛不同血药浓度与临床疗效及中毒的关系。方法采用荧光偏振免疫法(FPIA)测定236例住院病人的地高辛血药浓度,对不同血药浓度的患者进行分组,随访收集并分析其临床疗效。结果低于参考浓度组的41例中,有效率、再次住院率、死亡率及中毒率分别为19.5%、26.8%、12.2%、0.0%;0.50～0.90ng·mL-1(A组)的有效率、再次住院率、死亡率及中毒率分别为84.6%、26.2%、13.8%、0.0%;0.91～1.50ng·mL-1(B组)的有效率、再次住院率、死亡率及中毒率分别为87.9%、31.0%、19.0%、3.4%;1.51～2.00ng·mL-1(C组)的有效率、再次住院率、死亡率及中毒率分别为84.0%、44.0%、24.0%、12.0%;高于参考浓度组的有效率、再次住院率、死亡率及中毒率分别为42.6%、57.4%、36.2%、53.2%。结论地高辛治疗心衰的最佳血药浓度是0.50～0.90ng·mL-1。     

Plasma or serum in therapeutic drug monitoring and clinical toxicology

The relative merits of plasma and serum in blood analysis are reviewed. The expression plasma concentration is often used in the literature, although serum samples have been taken. In most cases serum and plasma concentrations of analytes are the same. The choice depends mostly on the policy of the hospital or the availability of the test tubes in the ward. Some of the advantages of plasma over serum are large volume, no delayed clotting, less risk of haemolysis. In addition, the sample is often suitable for both whole blood and plasma monitoring. Some of the disadvantages of plasma over serum are the (unknown) influence of the anticoagulant on the assay, on the protein binding and on the stability of the sample, the (unknown) influence of additives or impurities in the anticoagulants on the assay and on the concentration, the risk of the formation of small clots and dilution of the sample.     

Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications

Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over both injectable and enteral methods. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. For some drugs, this results in rapid onset of action via a more comfortable and convenient delivery route than the intravenous route. Not all drugs, however, can be administered through the oral mucosa because of the characteristics of the oral mucosa and the physicochemical properties of the drug. Several cardiovascular drugs administered transmucosally have been studied extensively. Nitroglycerin is one of the most common drugs delivered through the oral mucosa. Research on other cardiovascular drugs, such as captopril, verapamil and propafenone, has proven promising. Oral transmucosal delivery of analgesics has received considerable attention. Oral transmucosal fentanyl is designed to deliver rapid analgesia for breakthrough pain, providing patients with a noninvasive, easy to use and nonintimidating option. For analgesics that are used to treat mild to moderate pain, rapid onset has relatively little benefit and oral mucosal delivery is a poor option. Oral mucosal delivery of sedatives such as midazolam, triazolam and etomidate has shown favourable results with clinical advantages over other routes of administration. Oral mucosal delivery of the antinausea drugs scopolamine and prochlorperazine has received some attention, as has oral mucosal delivery of drugs for erectile dysfunction. Oral transmucosal formulations of testosterone and estrogen have been developed. In clinical studies, sublingual testosterone has been shown to result in increases in lean muscle mass and muscle strength, improvement in positive mood parameters, and increases in genital responsiveness in women. Short-term administration of estrogen to menopausal women with cardiovascular disease has been shown to produce coronary and peripheral vasodilation, reduction of vascular resistance and improvement in endothelial function. Studies of sublingual administration of estrogen are needed to clarify the most beneficial regimen. Although many drugs have been evaluated for oral transmucosal delivery, few are commercially available. The clinical need for oral transmucosal delivery of a drug must be high enough to offset the high costs associated with developing this type of product. Drugs considered for oral transmucosal delivery are limited to existing products, and until there is a change in the selection and development process for new drugs, candidates for oral transmucosal delivery will be limited.     

Amperometric biosensors for clinical and therapeutic drug monitoring: a review

The coupling of enzymes and electrode transducers permits the rapid and simple determination of endogeneous compounds and therapeutic drugs in clinical samples. New developments in the operation, miniaturization and microfabrication of electrochemical biosensors offer exciting possibilities for biomedical and pharmaceutical analysis. This review focuses on the current state of amperometric enzyme electrodes for biomedicine, with emphasis on recent advances, challenges and trends.     

氨磺必利片治疗药物监测及临床应用研究

目的分析氨磺必利的血药浓度与给药剂量、药物品种、性别、年龄和体重的相关性。方法用高效液相色谱-质谱联用法测定患者的氨磺必利血清谷浓度。回顾性查阅2016年至2017年我院1392例次住院患者氨磺必利的血药浓度监测记录,将浓度值、给药剂量、性别、年龄、厂家和合并用药等资料录入数据库,用SPSS 16. 0软件进行统计分析。结果成人患者服用氨磺必利后平均血药浓度为374. 75 ng·m L^-1,明显高于现有指南的参考范围,提示指南现有范围可能不适用于研究人群。氨磺必利最常见的药物不良反应为轻至中度锥体外系反应。结论老年患者、合并给药(丙戊酸、奥美拉唑和雷贝拉唑)可显著增加剂量校正后氨磺必利血药浓度,建议从低剂量开始给药,并密切注意监测血药浓度,减少发生药物不良反应的概率。性别、<18岁、厂家对该药的血药浓度影响不明显。     

儿科临床药师在治疗药物监测中的作用

治疗药物监测(Therapeutic Drug Monitoring,TDM)是近30年来形成的一门临床医学分支学科,也是临床药理学研究的重要内容之一.其通过运用各种灵敏的现代分析测定手段,定量分析生物样品(特别是患者用药后血浆或其它体液)中药物或其代谢产物的浓度.     

寡肽转运体在生理、药物转运的重要作用及临床相关性

寡肽转运体（PEPTs）属于溶质转运体（SLC）大家族,以H⁺梯度为驱动力,包括PEPT1和PEPT2。PEPT1是低亲和力、高容量转运蛋白,主要表达于小肠;而PEPT2是高亲和力、低容量的转运蛋白,主要在肾脏、脑和肺中表达,在生物体中分布较广。PEPTs除重吸收二肽和三肽以及维持脑中神经肽的稳态作用外,还能够吸收和处置许多重要的化合物,如一些氨基头孢菌素、血管紧张素转化酶抑制剂、抗病毒前药等,而且PEPTs也与一些肠道疾病和癌症相关。因此综述了PEPTs在生理、药物转运中的重要作用及临床相关性。     

Therapeutic drug monitoring of antidepressants: cost implications and relevance to clinical practice.

Despite evidence to support its potential benefit in clinical practice, therapeutic drug monitoring (TDM) is under-utilised and underdeveloped in the field of psychiatry. In antidepressant pharmacotherapy drug dose is emphasised as the critical treatment variable. However, dose in, and of, itself can be a strikingly misleading predictor of drug concentration and, hence, treatment effect. For antidepressant drugs, plasma concentrations at a given dose have been shown to vary in excess of 40-fold. The clinical relevance of this variability is that at a standard antidepressant dosage only some patients will have tissue drug concentrations associated with an optimal response whereas others will have either low, ineffective drug concentrations or unnecessarily high concentrations which may be poorly tolerated. Among clinicians and healthcare agencies there is an under-appreciation of the degree of pharmacokinetic variability found in patients and how that might impact on the patients response to pharmacotherapy. Hence there is a perception that TDM is an unnecessary, complicated and costly procedure. This is actually unfounded. There are data to suggest that TDM can favourably affect the outcome of antidepressant treatment by providing a rational alternative to the inherently slower, trial and error practice of dosage titration based on clinical response. It is unlikely that TDM will become a standard of care for all antidepressant agents and all patients. Therefore the question becomes for which antidepressant agents, for which patients and under what circumstances, is TDM more cost-effective than traditional dose titration. The use of TDM to optimise the efficient use of selected antidepressant agents could potentially free up healthcare resources to fund other equally deserving treatments. This article provides a discussion of the major classes of antidepressant drugs with regard to their pharmacological features that predict the utility of TDM in clinical practice. Recommendations are made for the practical application of TDM and the directions for further research.     

Structure,function and regulation of P-glycoprotein and its clinical relevance in drug disposition

1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR1 enable a re-evaluation of the biochemical evidence on the binding and transport of drugs by P-gp/MDR1.

2. P-gp/MDR1 is found in various human tissues in addition to being expressed in tumours cells. It is located on the apical surface of intestinal epithelial cells, bile canaliculi, renal tubular cells, and placenta and the luminal surface of capillary endothelial cells in the brain and testes.

3. P-gp/MDR1 confers a multi-drug resistance (MDR) phenotype to cancer cells that have developed resistance to chemotherapy drugs. P-gp/MDR1 activity is also of great clinical importance in non-cancer-related drug therapy due to its wide-ranging effects on the absorption and excretion of a variety of drugs.

4. P-gp/MDR1 excretes xenobiotics such as cytotoxic compounds into the gastrointestinal tract, bile and urine. It also participates in the function of the blood–brain barrier.

5. One of the most interesting characteristics of P-gp/MDR1 is that its many substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids and some antibiotics to macromolecules such as polysaccharides and proteins.

6. Quite a number of single nucleotide polymorphisms have been found for the MDR1 gene. These single nucleotide polymorphisms are associated with altered oral bioavailability of P-gp/MDR1 substrates, drug resistance, and a susceptibility to some human diseases.

7. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug–drug interactions with altered drug pharmacokinetics and response.

8. Further studies are warranted to explore the physiological function and pharmacological role of P-gp/MDR1.     

Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition

1. P-glycoprotein (P-gp/MDR1), one of the most clinically important transmembrane transporters in humans, is encoded by the ABCB1/MDR1 gene. Recent insights into the structural features of P-gp/MDR1 enable a re-evaluation of the biochemical evidence on the binding and transport of drugs by P-gp/MDR1. 2. P-gp/MDR1 is found in various human tissues in addition to being expressed in tumours cells. It is located on the apical surface of intestinal epithelial cells, bile canaliculi, renal tubular cells, and placenta and the luminal surface of capillary endothelial cells in the brain and testes. 3. P-gp/MDR1 confers a multi-drug resistance (MDR) phenotype to cancer cells that have developed resistance to chemotherapy drugs. P-gp/MDR1 activity is also of great clinical importance in non-cancer-related drug therapy due to its wide-ranging effects on the absorption and excretion of a variety of drugs. 4. P-gp/MDR1 excretes xenobiotics such as cytotoxic compounds into the gastrointestinal tract, bile and urine. It also participates in the function of the blood-brain barrier. 5. One of the most interesting characteristics of P-gp/MDR1 is that its many substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids and some antibiotics to macromolecules such as polysaccharides and proteins. 6. Quite a number of single nucleotide polymorphisms have been found for the MDR1 gene. These single nucleotide polymorphisms are associated with altered oral bioavailability of P-gp/MDR1 substrates, drug resistance, and a susceptibility to some human diseases. 7. Altered P-gp/MDR1 activity due to induction and/or inhibition can cause drug-drug interactions with altered drug pharmacokinetics and response. 8. Further studies are warranted to explore the physiological function and pharmacological role of P-gp/MDR1.     

急性肾盂肾炎致病菌的临床分析及药物疗效观察

目的：探讨急性肾盂肾炎致病菌的临床分析及药物疗效。方法2009年2月～2014年4月选择在我院诊治的急性肾盂肾炎患者80例,根据随机抽签原则分为哌拉西林/他唑巴坦治疗组与头孢地嗪治疗组各40例,头孢地嗪治疗组选择头孢地嗪治疗,哌拉西林/他唑巴坦治疗组选择注射用哌拉西林/他唑巴坦治疗。结果哌拉西林/他唑巴坦治疗组的治愈率为95.0%,头孢地嗪治疗组治愈率为80.0%,哌拉西林/他唑巴坦治疗组的治愈率明显高于头孢地嗪治疗组（P<0.05）。两组患者治疗期间都无严重并发症发生,随访至今,未见局部复发。结论急性肾盂肾炎的致病菌多为大肠杆菌,哌拉西林/他唑巴坦的应用治疗能提高治愈率,安全性好,值得推广应用。