Expert Opinion on Drug Metabolism & Toxicology

doi: 10.1517/17425255.2014.968318pmid: N/A

Italiano, Domenico; Spina, Edoardo; de Leon, Jose

doi: 10.1517/17425255.2014.956081pmid: 25196459

Introduction: Antiepileptic–antidepressant combinations are frequently used by clinicians; their pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions (DIs) have not been well studied but are frequently likely to be clinically relevant.Areas covered: This article provides a comprehensive review of PK DIs between antiepileptics and antidepressants. In the absence of PD DI studies, PD information on pharmacological mechanisms and studies on efficacy and safety of individual drugs are reviewed.Expert opinion: The clinical relevance of the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone and the inhibitory properties of valproic acid and some antidepressants are well understood; correction factors are provided if appropriate DI studies have been completed. More PK studies are needed for: i) antiepileptics with potent inductive effects for all recently approved antidepressants; ii) high doses of mild CYP3A4 inducers, such as clobazam, eslicarbazepine, oxcarbazepine, rufinamide and topiramate for reboxetine and vilazodone; iii) valproate as a possible inhibitor, mild inducer or both a mild inducer and competitive inhibitor of some antidepressants; and iv) inhibitory effects of long-term fluoxetine use on clobazam, lacosamide, phenobarbital, primidone, carbamazepine, felbamate, tiagabine and zonisamide. Possible synergistic or additive beneficial PD DIs in generalized anxiety disorder, chronic pain, migraine prophylaxis, weight control and menopausal symptoms need study.

Qian, Shuai; Wang, Qianwen; Zuo, Zhong

doi: 10.1517/17425255.2014.956080pmid: 25196358

Introduction: Recently, developing peptide-based drugs to treat CNS diseases has gained increasing attention in both academics and pharmaceutical industry. However, targeting delivery of peptides to brain is one of the most challenging problems faced in the treatment of CNS diseases.Areas covered: After explaining the brain barriers limiting the delivery of peptides, the current review focuses on summarizing the most promising approaches for the enhancement of peptide and brain uptake, including delivery via alternative routes of administrations or using nanocarriers or intranasal administration of nanocarriers loaded with peptide. In addition, the biopharmaceutic, pharmacokinetic and pharmacodynamic details of several successful peptide-based CNS drugs are highlighted.Expert opinion: Although using nanocarriers or delivery via alternative routes could improve to a certain extent the brain uptake of peptides, the magnitude of changes remains moderate. Alternatively, intranasal administration of nanocarriers loaded with peptide has been demonstrated to be an effective approach for CNS-targeted delivery of peptides.

Tajti, János; Csáti, Anett; Vécsei, László

doi: 10.1517/17425255.2014.963554pmid: 25253587

Introduction: Migraine is a common, paroxysmal, and disabling primary headache with a high personal and socioeconomic impact. It involves ∼ 16% of the general population. During the years, a number of hypotheses have been put forward concerning the exact pathomechanism, but the final solution is still undiscovered.Areas covered: Although the origin is enigmatic, parallel therapeutic efforts have been developed. Current attack therapy does not meet the expectations of the patients or the doctors. This article, based on a PubMed search, reviews the novel pharmacological possibilities that influence the peripheral and central sensitization involved in the disease.Expert opinion: In order to overcome the therapeutic insufficiency, a calcitonin gene-related peptide receptor antagonist without the side-effect of liver transaminase elevation is required. Another therapeutic option is to develop a neurally acting antimigraine agent, such as a serotonin-1F receptor agonist, with low adverse central nervous system events. Development of a potent dopamine receptor antagonist is necessary to diminish the premonitory symptoms of migraine. A further option is to decrease the headache intensity with a pituitary adenylate cyclase-activating polypeptide type 1 receptor blocker which can cross the blood-brain barrier. Finally, synthetic kynurenine analogues are required to block the pain transmission in the activated trigeminal system.

Wang, Yue-Ming; Chai, Sergio C; Brewer, Christopher T; Chen, Taosheng

doi: 10.1517/17425255.2014.963555pmid: 25252616

Introduction: The liver plays a central role in transforming and clearing foreign substances. The continuous exposure of the liver to xenobiotics sometimes leads to impaired liver function, referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) tightly regulates the expression of genes in the hepatic drug-clearance system and its undesired activation plays a role in DILI.Areas covered: This review focuses on the recent progress in understanding PXR-mediated DILI and highlights the efforts made to assess and manage PXR-mediated DILI during drug development.Expert opinion: Future efforts are needed to further elucidate the mechanisms of PXR-mediated liver injury, including the epigenetic regulation and polymorphisms of PXR. Novel in vitro models containing functional PXR could improve our ability to predict and assess DILI during drug development. PXR inhibitors may provide chemical tools to validate the potential of PXR as a therapeutic target and to develop drugs to be used in the clinic to manage PXR-mediated DILI.

Dietrich, Christoph G; Geier, Andreas

doi: 10.1517/17425255.2014.963553pmid: 25260651

Introduction: The liver is the central place for the metabolism of drugs and other xenobiotics. In the liver cell, oxidation and conjugation of compounds take place, and at the same time, bile formation helps in extrusion of these compounds via the biliary route. A large number of transporters are responsible for drug uptake into the liver cell and excretion into bile or efflux to the sinusoidal blood.Areas covered: Genetic variants of these transporters and their transactivators contribute to changes in drug handling and are also responsible for cholestatic syndromes of different severity. This review summarizes the current knowledge regarding the influence of these genetic changes. The review covers progressive hereditary cholestatic syndromes as well as recurrent or transient cholestatic syndromes such as drug-induced liver injury, intrahepatic cholestasis of pregnancy, and benign recurrent intrahepatic cholestasis.Expert opinion: Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.

Gómez-Lechón, M José; Tolosa, Laia; Conde, Isabel; Donato, M Teresa

doi: 10.1517/17425255.2014.967680pmid: 25297626

Introduction: The liver is the most important target for drug-induced toxicity. This vulnerability results from functional liver features and its role in the metabolic elimination of most drugs. Drug-induced liver injury is a significant leading cause of acute, chronic liver disease and an important safety issue when developing new drugs.Areas covered: This review describes the advantages and limitations of hepatic cell-based models for early safety risk assessment during drug development. These models include hepatocytes cultured as monolayer, collagen-sandwich; emerging complex 3D configuration; liver-derived cell lines; stem cell-derived hepatocytes.Expert opinion: In vitro toxicity assays performed in hepatocytes or hepatoma cell lines can potentially provide rapid and cost–effective early feedback to identify toxic candidates for compound prioritization. However, their capacity to predict hepatotoxicity depends critically on cells’ functional performance. In an attempt to improve and prolong functional properties of cultured cells, different strategies to recreate the in vivo hepatocyte environment have been explored. 3D cultures, co-cultures of hepatocytes with other cell types and microfluidic devices seem highly promising for toxicological studies. Moreover, hepatocytes derived from human pluripotent stem cells are emerging cell-based systems that may provide a stable source of hepatocytes to reliably screen metabolism and toxicity of candidate compounds.

LLerena, Adrián; Naranjo, Maria Eugenia G; Rodrigues-Soares, Fernanda; Penas-LLedó, Eva M; Fariñas, Humberto; Tarazona-Santos, Eduardo

doi: 10.1517/17425255.2014.964204pmid: 25316321

Introduction: The frequency of CYP2D6 alleles, related to either a lack of or increased enzymatic activity, which may lead to poor metabolism (PM) or ultrarapid metabolism (UM), can vary across ethnic groups and hence across geographic regions.Areas covered: Worldwide original research papers on CYP2D6 allelic frequencies, metabolic phenotype frequencies measured with a probe drug, and/or genotype frequencies that studied > 50 healthy volunteers, were included in analyses to describe the distributions of alleles, phenotypes predicted from genotypes (predicted poor metabolizers [gPMs], predicted ultrarapid metabolizers [gUMs]) and metabolic phenotypes (mPMs, mUMs) across ethnic groups and geographic regions. The analysis included 44,572 individuals studied in 172 original research papers.Expert opinion: As of today, Africa and Asia are under-represented in this area relative to the total number of their inhabitants, so that further studies in these regions are warranted. The CYP2D6*4 allele frequency was higher in Caucasians, CYP2D6*10 in East Asians, CYP2D6*41 and duplication/multiplication of active alleles in Middle Easterns, CYP2D6*17 in Black Africans and CYP2D6*29 in African Americans, than in other ethnic groups. Overall, gPMs and mPMs are more frequent among Caucasians, and gUMs among Middle Easterns and Ethiopians. However, mUMs could not be evaluated because only two studies were found presenting this information. Further studies including mUMs are thus warranted. There is a correspondence between gPMs and mPMs, but the few studies of mUMs meant that their relationship with gUMs could not be demonstrated. Finally, evolutionary aspects of the CYP2D6 allele distribution appear to support the Great Human Expansion model.

Rangel, Erika B

doi: 10.1517/17425255.2014.964205pmid: 25255841

Introduction: With further reduction in surgical complications and improvement in immunosuppressive protocols, pancreas transplant offers excellent outcomes for patients with diabetes. However, long-term survival of pancreas allograft is affected not only by rejection but also by immunosuppressive regimen toxicity.Areas covered: This article reviews the existing literature and knowledge of tacrolimus toxicity and focuses on its diabetogenic effect after pancreas transplant. Some clinically relevant drug–drug interactions with glucocorticoids and sirolimus are also highlighted. This review also summarizes the diabetogenic mechanisms of tacrolimus, the alternatives to minimize these effects, and the main differential diagnosis of hyperglycemia after pancreas transplant.Expert opinion: Tacrolimus is a potent calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus can induce β-cell apoptosis, decrease insulin exocytosis and reduce insulin gene transcription, which ultimately lead to impaired functional β-cell mass after pancreas transplant. Furthermore, insulin resistance can exacerbate the diabetogenic effect of tacrolimus due to inhibition of insulin gene transcription and β-cell proliferation. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Chan, Stephen L; Ma, Brigette BY

doi: 10.1517/17425255.2014.970169pmid: 25316322

Introduction: Regorafenib is a multi-targeted kinase inhibitor that has been approved recently for the treatment of certain gastrointestinal (GI) cancers. This review examines the scientific evidence on the efficacy and safety of this agent in Phase I to III studies.Areas covered: A literature review was performed based on published studies from PubMed and abstracts from international conferences.Expert opinion: Regorafenib has expanded the treatment options of patients with treatment-refractory gastrointestinal stromal tumor (GIST) and metastatic colorectal cancer (CRC). Ongoing studies are now investigating the activity of regorafenib as earlier line of therapy in CRC as monotherapy or in combination with chemotherapy. In the next 5 years, the activity of regorafenib will be further defined in other cancers such as renal cell cancer (RCC), hepato-biliary and upper GI cancers. In terms of safety, clinical trials suggest that the incidence and severity of toxicities may be higher in certain populations such as those with RCC or GIST. However, most of the common toxicities of regorafenib could be managed with dose modification without resorting to permanent drug discontinuation. Education of both patients and clinicians is thus important in minimizing treatment-related toxicities and improving drug compliance.