Current Drug Metabolism (v.17, #7)

Meet Our Associate Editor by Jasminder Sahi (627-627).

Background: The interest in administering drugs by intranasal route is currently increasing, particularly because it has shown to ensure drug therapeutic action by a rapid systemic absorption through the respiratory mucosa and/or a direct delivery of some molecules into the brain through the olfactory mucosa. Nevertheless, although intranasal administration avoids the first-pass hepatic biotransformation, several enzymes as well as efflux transporters can be found in the mammalian nasal epithelium.
Methods: This work reviewed the expression and localization of the drug-metabolizing enzymes and efflux transporters in the mammalian nasal mucosa epithelium, as well as their influence on the pharmacokinetic and pharmacodynamic profiles of specific drugs, using one hundred and thirty five peer-reviewed papers undertaken from MEDLINE database, including review and research papers.
Results: Most of the studies analyzed corroborate that oxidative and conjugative enzymes as well as multidrug resistance proteins and multidrug resistance-associated proteins efflux transporters are expressed in the nasal cavity, particularly in olfactory and respiratory mucosae, determining the access of drugs to central nervous system and bloodstream. Nonetheless, besides their well-documented anatomic location, either in laboratory animals or humans, there is still a lack of experimental information regarding the substrates of these enzymes and efflux transporters at the nasal cavity.
Conclusion: The knowledge herein discussed important not only to select the drugs with better potential to be administered by intranasal route but also to optimize drug formulations, in which inhibitors of enzymes or efflux transporters may be included to increase drug systemic and central delivery.

The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity by Constanza Morén, Diana Luz Juárez-Flores, Francesc Cardellach, Glòria Garrabou (648-662).
Background: Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient.
Objectives: The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide.
Methods: We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs.
Results: One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. Conclusions: Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.

Implications of Kidney Disease on Metabolic Reduction by Osama Y. Alshogran, Thomas D. Nolin (663-672).
Chronic kidney disease (CKD) modulates the nonrenal clearance of drugs by altering their metabolism and/or transport. While the effects of CKD on pathways of oxidative and conjugative metabolism in the liver are generally understood, the impact of CKD on hepatic reduction is not. Reduction is a critically important pathway for the metabolism of several drugs and endogenous compounds. Multiple clinical pharmacokinetic studies have reported changes in the disposition of hepatic reductase drug substrates in patients with CKD. More recently, data from experimental studies have shown that kidney disease alters the functional expression of hepatic reductases. Together, these data suggest that kidney disease may impair the nonrenal clearance of drugs mediated by reductive pathways. This review synthesizes the current evidence available regarding the effect of CKD on hepatic reduction. Areas for future investigations are also highlighted. The growing knowledge of the impact of impaired kidney function on nonrenal drug clearance may facilitate optimal drug therapy in this patient population.

Background: In drug metabolism reactions, it has become increasingly important to measure Michaelis constants (Km), which are used for a variety of purposes, including identification of enzymes involved in drug metabolism, prediction of drug-drug interactions, etc. Cytochrome P450s (CYPs) comprise a super family of major human enzymes responsible for drug metabolism. Hence, computational prediction of Km in CYP-mediated reactions facilitates drug development in an efficient and economical way.
Methods: In this study, we firstly constructed a large dataset of ten CYP isoforms associated with 169 binding substrates, and 210 experimental Km values in CYP-mediated reactions. To predict Km of substrates metabolized by various CYP isoforms, we developed a general prediction model by using resilient back-propagation neutral network algorithm, based on the structural and physicochemical properties of the substrates and the metabolic specificity of the enzymes.
Results: The predictive Km values achieve a squared cross-validation correlation coefficients (Q2) of 0.73 with the experimental values, which is better than that of the existing models. Moreover, our model can predict Km values of the compounds metabolized by a wide range of CYP isoforms.
Conclusion: This tool will be useful in large-scale drug screening studies for CYP enzymes and helpful in the drug design and development.

Drug Interactions with Angiotensin Receptor Blockers: Role of Human Cytochromes P450 by Ruirui Yang, Zhiqiang Luo, Yang Liu, Mohan Sun, Ling Zheng, Yingying Chen, Yanping Li, Hao Wang, Lingzhu Chen, Ming Wu, Huihui Zhao (681-691).
Background: Angiotensin receptor blockers (ARBs) are the most recent class of agents for the treatment of hypertension. However, ARBs may cause a low incidence of headache, upper respiratory infection, back pain, muscle cramps, fatigue, dizziness, and many other side effects. In some cases, such toxicity is associated with pharmacokinetic alterations.
Methods: The cytochrome P450 (CYP) enzyme system plays an important role in a lot of clinically important pharmacokinetic drug interactions. To identify relevant studies on drug-drug and food-drug pharmacokinetic interactions with the ARBs, a literature search of Google Scholar was performed from January 1994 to June 2015, with the following keywords: 'losartan', 'valsartan,' 'candesartan,' 'irbesartan,' 'telmisartan,' 'eprosartan,' 'olmesartan,' and 'azilsartan', combined with the keyword 'pharmacokinetic interactions' and 'CYP'.
Results: Based on the literatures published, it has been demonstrated that pharmacokinetic interactions of losartan with other agents are mainly via CYP2C9- and CYP3A4-mediated, the role played by CYP enzyme system in the metabolism of valsartan, candesartan, irbesartan, and azilsartan appears modest, and cytochrome P450 system has no influence on the metabolism of telmisartan, eprosartan, olmesartan. Therefore, according to these pharmacokinetic findings, no dosage adjustment is recommended when eprosartan, telmisartan and olmesartan are combined with other pharmacological agents in patients with hypertension.
Conclusion: This review summarize the available data on cytochrome P450 - related drug-drug interactions reported in the literature for the eight ARBs. Knowledge of the pharmacokinetic properties of the ARBs should allow the avoidance of the majority of drug interactions without compromising therapeutic benefits.

Stereoselective Pharmacodynamics and Pharmacokinetics of Proton Pump Inhibitors by Zhi-Cheng Yang, Feng Yu, Yong-Qing Wang, Ji-Fu Wei (692-702).
Background: Proton pump inhibitors (PPIs) are a group of gastric acid suppressing drugs, they work by irreversibly blocking the H+/K+ ATPase. The structure of PPIs is similar. They all have a similar core with a sulphur atom chiral center combined with different substituent groups. In relation to the sulphur atom chiral center, the pharmacodynamics, pharmacokinetics are diverse between the racemates and their stereoisomers. But there are no reviews outlining the stereoselective pharmacodynamics and pharmacokinetics in PPIs. This review aims to compare the differences between the stereoisomers of PPIs in their pharmacodynamics and pharmacokinetics parameters. And exploring the development directions of PPIs at present.
Methods: We undertook a search of PubMed databases for PPI research literature including reviews, clinical studies, letters and books, in recent 20 years. The citied papers were high quality, which were carefully screened by authors using standard tools. The data of the pharmacodynamics and pharmacokinetics parameters were selected from the retrieved papers, then making generalization and summary.
Results: Ninety-three papers were included in the review, mainly from East Asia, America and Europe. All these papers involved the reviews of PPIs, the pharmacodynamics studies of PPIs and the pharmacokinetics studies of PPIs. Finally, omeprazole, lansoprazole, pantoprazole, rebeprazole and pantoprazole with their enantiomers were discussed in this paper.
Conclusion: The findings of this review confirm the differences of pharmacodynamics and pharmacokinetics in the racemates and the stereoisomer of PPIs. Providing longer duration, faster time of onset and better nocturnal gastric acid secretion control are the development directions of new generation PPIs. But, due to debate on the necessity and superiority of these new drugs, more validation studies are needed.

Background: During the last few years there has been a growing interest in research focused on the metabolism of steroid hormones despite that the study of metabolic hormone pathways is still a difficult and demanding task because of low steroid concentrations and a complexity of the analysed matrices. Thus, there has been an increasing interest in the development of new, more selective and sensitive methods for monitoring these compounds in biological samples.
Methods: A lot of bibliographic databases for world research literature were structurally searched using selected review question and inclusion/exclusion criteria. Next, the reports of the highest quality were selected using standard tools (181) and they were described to evaluate the advantages and limitations of different approaches in the measurements of the steroids and their metabolites.
Results: The overview of the analytical challenges, development of methods used in the assessment of the metabolic pathways of steroid hormones, and the priorities for future research with a special consideration for liquid chromatography (LC) and capillary electrophoresis (CE) techniques have been presented. Moreover, many LC and CE applications in pharmacological and psychological studies as well as endocrinology and sports medicine, taking into account the recent progress in the area of the metabolic profiling of steroids, have been critically discussed.
Conclusion: The latest reports show that LC systems coupled with mass spectrometry have the predominant position in the research of steroid profiles. Moreover, CE techniques are going to gain a prominent position in the diagnosis of hormone levels in the near future.

Population Pharmacokinetics of Phenytoin Based on NONMEM in Patients with Intracranial Tumor During the First Week of Post-Craniotomy by Zhong-dong Li, Meng Liu, Liang Li, Jing-hai Wan, Zhaojin Lei, Yong-an Huang (721-728).
Background: It was reported that phenytoin can prevent early post traumatic seizures. The present study aims to establish a population pharmacokinetic (PPK) model of oral phenytoin in patients with intracranial tumor during the early periods, the first week, of post-craniotomy to optimize phenytoin dosage regimen.
Methods: Sixty-two patients with intracranial tumor were genotyped for CYP2C9 and CYP2C19 by real time PCR (TaqMan probe), and subsequently their phenytoin dosage regimens were designed according to the results of previous literature. A total of 123 plasma concentrations of oral phenytoin during the early periods of post-craniotomy, patient demographics, clinical biochemical indicators and drug combination were collected. A PPK model was performed using the nonlinear mixed effects model (NONMEM) program.
Results: The final PPK model equations of oral phenytoin were found to be as follows: for patients with CYP2C9 *1/*1, Vmax=22.66(BWT/60.96)0.454(mg/h) and Km =4.03 (mg/L); for patients with CYP2C9*1/*3, Vmax = 16.65(BWT / 60.96 )0.454 (mg/h) and Km =5.96 (mg/L). The PPK model was proved to be stable and effective by bootstrap method. Clinical individualized dosage regimens of additional 50 patients were designed by above PPK model. Concentrations on the morning of Day 7 (D7 concentrations) of 56% (28/50) of these patients were within the therapeutic range (1020mg/L), which demonstrated better improvement than that of 37.1% of above 62 patients.
Conclusion: The final PPK model of oral phenytoin may be helpful to design phenytoin individualized dosage regimen at the early stage of post-craniotomy when characteristics of patients meet these of subpopulation in the study.