Differences In Drug Metabolism Research Articles

Addressing Race, Ethnicity, and Structural Inequality in Pharmacology Education and Assessment

OBJECTIVESocial determinants of health, including race, ethnicity, and gender, represent important factors in health care delivery and patient outcomes, and contribute to health disparities. Pharmacology, as an integrated discipline, lies at the nexus between foundational science and clinical practice, providing a platform for educators to discuss the impact of social determinants on patient outcomes. Our goal is to create a framework that provides guidance for topics in pharmacotherapeutics for educators, learners, and providers to use in promoting antiracism in medical curricula.METHODSThrough iterative discussions, we developed a conceptual framework that includes topics taught across medical schools, such as drug metabolism, pharmacogenomics, adverse drug reactions, prescribing guidelines, factors affecting medication adherence, pain management, and therapeutic outcomes. Under each topic, we describe how social constructs such as race, ethnicity, and gender can impact pharmacology and therapeutic outcomes.RESULTSLiterature reports show that some topics in pharmacology education have already established cultural competency and should be adopted widely by all pharmacology educators, e.g., using more appropriate terminology for drug reactions such as vancomycin‐infusion reaction. Other topics are less established, so a more nuanced discussion with students is required. Society guidelines for managing diseases such as hypertension include prescribing recommendations based on race, with which learners are expected to be familiar as they enter clinical training but are actively being debated. Similarly, inter‐ethnic differences in drug metabolism are often reported as a function of genetic polymorphisms without considering non‐genetic factors.CONCLUSIONSWe have developed a conceptual framework for promoting antiracism in pharmacology education by categorizing topics based on those where cultural competencies are clearly established and those where a more nuanced discussion is required with learners, as well as identifying and reducing bias in assessment. These are generalizable across health professions in which pharmacology education is a discipline in the curriculum.

The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children.

The limit for possible survival after extremely preterm birth has steadily improved and consequently, more premature neonates with increasingly lower gestational age at birth now require care. This specialized care often include intensive pharmacological treatment, yet there is currently insufficient knowledge of gestational age dependent differences in drug metabolism. This potentially puts the preterm neonates at risk of receiving sub-optimal drug doses with a subsequent increased risk of adverse or insufficient drug effects, and often pediatricians are forced to prescribe medication as off-label or even off-science. In this review, we present some of the particularities of drug disposition and metabolism in preterm neonates. We highlight the challenges in pharmacometrics studies on hepatic drug metabolism in preterm and particularly extremely (less than 28 weeks of gestation) preterm neonates by conducting a scoping review of published literature. We find that >40% of included studies failed to report a clear distinction between term and preterm children in the presentation of results making direct interpretation for preterm neonates difficult. We present summarized findings of pharmacokinetic studies done on the major CYP sub-systems, but formal meta analyses were not possible due the overall heterogeneous approaches to measuring the phase I and II pathways metabolism in preterm neonates, often with use of opportunistic sampling. We find this to be a testament to the practical and ethical challenges in measuring pharmacokinetic activity in preterm neonates. The future calls for optimized designs in pharmacometrics studies, including PK/PD modeling-methods and other sample reducing techniques. Future studies should also preferably be a collaboration between neonatologists and clinical pharmacologists.

SAFETY MATTERS: THE TROUBLED AND FINALLY SUCCESSFUL STORY OF DIHYDROPYRIMIDINE DEHYDROGENASE PHARMACOGENETIC TEST IN CANCER PATIENTS

Pharmacogenetics investigates the molecular basis of inter-individual differences in drug metabolism and response. Sequence variations in genes encoding for metabolic enzymes may influence drug’s pharmacokinetics and/or pharmacodynamics, resulting in reduced efficacy and/or adverse drug reactions. The dihydropyrimidine dehydrogenase (DPD) deficiency is a clear example of how gene variants may affect fluoropyrimidines metabolism, and its … Continued

Normal variation of the gut microbiota affects hepatic cytochrome P450 activity in mice.

Several studies revealed that substantial artificial changes in the gut microbiota resulted in modification of hepatic cytochrome P450 3a (Cyp3a) in mice. Consequently, we hypothesized that “normal” variation of the gut microbiota might also alter hepatic Cyp activity and lead to individual differences in drug metabolism. Therefore, this study investigated the effects of normal gut microbiota variation on hepatic Cyp activity under the same genetic and environmental conditions using ex‐germ‐free mice. Using the feces of three breeder BALB/c mice (Jcl, Slc, and Crj), germ‐free BALB/cYit mice were conventionalized (Yit‐Jcl, Yit‐Slc, and Yit‐Crj). The gut microbiota composition and hepatic Cyp activity of these donors and recipients were evaluated. 16S rRNA sequencing revealed clear differences of the gut microbiota among donors and among recipients. Cyp3a activity was significantly higher in Slc mice than in Jcl and Crj mice. Notably, among recipients, Cyp3a activity was significantly higher in Yit‐Slc and Yit‐Crj mice than in Yit‐Jcl mice. Cyp2b activity was significantly higher in Slc mice than in Jcl and Crj mice. Cyp2b activity was significantly higher in Yit‐Slc mice than in Yit‐Jcl mice. Additionally, in correlation analysis, some genera displayed significant positive or negative correlations with Cyp activity, particular the strong positive correlation between Clostridium sensu stricto 1 with Cyp3a activity. In conclusion, this study demonstrated that normal variation of the gut microbiota affected hepatic Cyp3a and Cyp2b activity, which might result in individual differences of drug metabolism.

Autonomic and cardiac evaluation upon sub-therapeutic doxorubicin administration

Abstract Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged >3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p<0.05) DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

Variability of CYP2C8 Polymorphisms in Three Jordanian Populations: Circassians, Chechens and Jordanian-Arabs.

CYP2C8 is a member of Cytochrome P450 enzymes system. It plays an important role in metabolizing a wide range of exogenous and endogenous compounds. CYP2C8 is involved in the metabolism of more than 100 drugs, typical substrates include: anticancer agents, antidiabetic agents, antimalarial agents, lipid lowering drugs and many others that constitute 20% of clinically prescribed drugs. Genetic variations of CYP2C8 have been reported with different frequencies in different populations. These genetic polymorphisms can lead to differences in the efficacy and safety of different types of medications metabolized by CYP2C8. The aim of this study was to investigate the allele frequencies of CYP2C8*3 (rs10509681 and rs11572080) and CYP2C8*4 (rs1058930) polymorphisms in three populations living in Jordan; Circassians and Chechens and Jordanian-Arabs and compare those frequencies with other populations. A total of 200 healthy Jordanians, 93 Circassians and 88 Chechens were included in this study. Genotyping of CYP2C8*3 and CYP2C8*4 polymorphisms was done by using polymerase chain reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP). Using the Chi-square test, we found that the prevalence of CYP2C8*3 and *4 among the three populations were significantly different. Moreover, the mutant allele CYP2C8*3 (416A) was only detected in the Jordanian-Arab population with an allele frequency of 0.082, while the mutant allele CYP2C8*4 (792G) was detected with frequencies of 0.065, 0.122, 0.017 in Jordanian-Arabs, Circassians and Chechens, respectively. As our results show, CYP2C8*3 was undetectable in our Circassians and Chechens samples, on the other hand, Circassians had the highest allele frequency of CYP2C8*4 compared to Chechens and Jordanian-Arabs. These genetic variations of the gene encoding the CYP2C8 drug metabolizing enzymes can lead to clinical differences in drug metabolism and ultimately variations in drug effectiveness and toxicities. This study provides evidence for the importance of personalized medicine in these populations and can be the foundation for future clinical studies.

MetMax Human Hepatocyte/HEK Cytotoxic Reactive Metabolite Assay as a Potential In Vitro Experimental System for the Identification of DILI Drugs

In drug development, it is important to identify drug candidates where drug metabolism plays key roles in their toxicity. Major reasons for the identification of drug candidates with metabolism-dependent toxicity are as follows: 1. Safety profiles determined in preclinical animal species may not accurately predict human effects due to species difference in drug metabolism; and 2. idiosyncratic drug toxicity may occur in individuals due to enhanced metabolic activation or compromised detoxification. We recently developed a novel in vitro hepatocyte system, the MetMax Human Hepatocyte (MMHH) system with permeabilized human hepatocytes supplemented with metabolic cofactors, for the evaluation of drug metabolism. The permeabilization treatment removes the plasma membrane as a barrier for drug diffusion into the hepatocytes, and the diffusion of the metabolites of the hepatocytes. A further advantage of MMHH is that cytotoxicity of the intended substrate would not affect drug metabolism, a challenge often encountered in the evaluation of metabolism of toxic drugs in intact hepatocytes. We report here the development of the MMHH/HEK assay for the evaluation of metabolic activation and detoxification of toxic drugs. In this assay, drug toxicity is quantified in a drug metabolism incompetent target cell line (HEK293) in the presence of absence of MMHH as an exogenous metabolic activating system, and in the presence of selective cofactors for the evaluation of key metabolic activation and detoxification pathways. As a proof-of-concept study, the MMHH/HEK assay was applied in the the evaluation of the model metabolically-activated drugs that are known to be associated with severe drug induced liver injuries (DILI) - acetaminophen, cyclophosphamide, and troglitazone. Our results showed that the cytotoxicity of these model DILI drugs was enhanced in the presence of MMHH supplemented with NADPH, thereby confirming the role of oxidative metabolism in metabolic activation. Furthermore, supplementation of NADPH with reduced glutathione (GSH), a physiologically relevant detoxifying conjugating cofactor for reactive metabolites, led to significant attenuation of cytotoxicity, demonstrating that these model drugs were metabolized by hepatocytes to to reactive, cytotoxic metabolites. Supplementation with UDPGA and PAPS also attenuated the in vitro cytotoxicity of these model drugs in the MMHH/HEK assay, demonstrating the involvement of glucuronidation and sulfation conjugating pathways in toxification. Troglitazone cytotoxicity in the MMHH/HEK assay was found to be higher than that observed for the known less hepatotoxic analogs, rosiglitazone and pioglitazone. Our results suggest that MMHH/HEK assay can be applied towards the evaluation of metabolic activation and detoxification and the identification of drugs with idiosyncratic DILI potential.

Hydrolase activities of cynomolgus monkey liver microsomes and recombinant CES1, CES2, and AADAC

The cynomolgus monkey is a nonhuman primate that is often used for pharmacokinetic and toxicokinetic studies of new chemical entities. Species differences in drug metabolism are obstacles for the extrapolation of animal data to humans. This study aimed to characterize hydrolase activities for typical compounds by cynomolgus monkey liver microsomes and recombinant monkey carboxylesterases (CES1 and CES2) and arylacetamide deacetylase (AADAC) compared with the activities in humans. To estimate the contribution of each hydrolase, the ratios of the expression level of each hydrolase in the liver microsomes and recombinant systems were used. For almost all of the tested human CES1 substrates, hydrolase activities in cynomolgus monkey liver microsomes tended to be lower than those in human liver microsomes, and recombinant cynomolgus monkey CES1 showed catalytic activity, but not for all substrates. For human CES2 substrates, hydrolase activities in cynomolgus monkey liver were higher than those in human liver microsomes, and recombinant monkey CES2 was responsible for their hydrolysis. Among human AADAC substrates, phenacetin was mainly hydrolyzed by monkey AADAC, whereas indiplon and ketoconazole were hydrolyzed by AADAC and other unknown enzymes. Flutamide was hydrolyzed by monkey CES2, not by AADAC. Rifamycins were hardly hydrolyzed in monkey liver microsomes. In conclusion, this study characterized the hydrolase activities of cynomolgus monkeys compared with those in humans. The findings would be helpful for pharmacokinetic or toxicokinetic studies of new chemical entities whose main metabolic pathway is hydrolysis.

Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants

Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (Ki) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 16.1 μM, respectively. The Ki values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.2-fold higher than those for rCYP3A4.1, respectively, whereas the Ki value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the Ki values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4.

Gender and Psychotropic Poisoning in the USA

Background: This study focuses on gender-based trends in psychotropic agent poisoning across a 17-year span. The goal of the study was to determine whether there are statistically significant differences in the characteristics of male and female hospital stays for psychotropic agent poisoning. Methods: We used the Healthcare Cost and Utilization Project (HCUP) national database to perform a retrospective cohort study analyzing trends for poisoning by psychotropic agents in males and females between 1997 and 2014. Results: Between 1997 and 2014, HCUP recorded a total of 1,368,649 psychotropic agent poisoning discharges. The overall number of discharges increased from 62,148 to 82,905 (P < 0.001). The average age at discharge increased from 37.36 to 40.85 years (P < 0.001). As the average length of stay increased from 2.3 to 3.2 days (P < 0.001), hospital charges increased from $6,357 to $27,892 (P < 0.001). Across the study period, the number of in-hospital deaths increased from 468 to 755 (P < 0.001). In each year of the study, both number of discharges and average age were found to be greater for females than for males (P < 0.001). Conclusions: Female discharges were consistently higher than male discharges, suggesting that female patients were more likely to experience psychotropic poisoning than male patients. This may possibly be due to a greater number of women being prescribed psychotropic medications, in concordance with higher rates of mood and anxiety disorders. Additionally, there exist notable differences in drug metabolism that should be considered to prevent overprescribing. J Neurol Res. 2020;10(6):220-225 doi: https://doi.org/10.14740/jnr640

Transcriptional and post-transcriptional regulation of the pregnane X receptor: a rationale for interindividual variability in drug metabolism.

The pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-regulated transcription factor originally described as a master regulator of xenobiotic detoxification. Later, however, PXR was also shown to interact with endogenous metabolism and to be further associated with various pathological states. This review focuses predominantly on such aspects, currently less covered in literature, as the control of PXR expression per se in the context of inter-individual differences in drug metabolism. There is growing evidence that non-coding RNAs post-transcriptionally regulate PXR. Effects on PXR have especially been reported for microRNAs (miRNAs), which include miR-148a, miR-18a-5p, miR-140-3p, miR-30c-1-3p and miR-877-5p. Likewise, miRNAs control the expression of both transcription factors involved in PXR expression and regulators of PXR function. The impact of NR1I2 genetic polymorphisms on miRNA-mediated PXR regulation is also discussed. As revealed recently, long non-coding RNAs (lncRNAs) appear to interfere with PXR expression. Reciprocally, PXR activation regulates non-coding RNA expression, thus comprising another level of PXR action in addition to the direct transactivation of protein-coding genes. PXR expression is further controlled by several transcription factors (cross-regulation) giving rise to different PXR transcript variants. Controversies remain regarding the suggested role of feedback regulation (auto-regulation) of PXR expression. In this review, we comprehensively summarize the miRNA-mediated, lncRNA-mediated and transcriptional regulation of PXR expression, and we propose that deciphering the precise mechanisms of PXR expression may bridge our knowledge gap in inter-individual differences in drug metabolism and toxicity.

Hepatic Transcript Profiles of Cytochrome P450 Genes Predict Sex Differences in Drug Metabolism.

Safety assessments of new drug candidates are an important part of the drug development and approval process. Often, possible sex-associated susceptibilities are not adequately addressed, and better assessment tools are needed. We hypothesized that hepatic transcript profiles of cytochrome P450 (P450) enzymes can be used to predict sex-associated differences in drug metabolism and possible adverse events. Comprehensive hepatic transcript profiles were generated for F344 rats of both sexes at nine ages, from 2 weeks (preweaning) to 104 weeks (elderly). Large differences in the transcript profiles of 29 drug metabolizing enzymes and transporters were found between adult males and females (8–52 weeks). Using the PharmaPendium data base, 41 drugs were found to be metabolized by one or two P450 enzymes encoded by sexually dimorphic mRNAs and thus were candidates for evaluation of possible sexually dimorphic metabolism and/or toxicities. Suspension cultures of primary hepatocytes from three male and three female adult rats (10–13 weeks old) were used to evaluate the metabolism of 11 drugs predicted to have sexually dimorphic metabolism. The pharmacokinetics of the drug or its metabolite was analyzed by liquid chromatography/tandem mass spectrometry using multiple reaction monitoring. Of those drugs with adequate metabolism, the predicted significant sex-different metabolism was found for six of seven drugs, with half-lives 37%–400% longer in female hepatocytes than in male hepatocytes. Thus, in this rat model, transcript profiles may allow identification of potential sex-related differences in drug metabolism.SIGNIFICANCE STATEMENTThe present study showed that sex-different expression of genes coding for drug metabolizing enzymes, specifically cytochrome P450s, could be used to predict sex-different drug metabolism and, thus, provide a new tool for protecting susceptible subpopulations from possible adverse drug events.

Spotting species-specific toxicity

Drug Testing Candidate drug testing using standard preclinical models cannot accurately predict which compounds are likely to cause drug-induced liver injury in humans. To improve selection of promising drug candidates, Jang et al. developed Liver-Chips, which consist of rat, dog, or human hepatocytes, endothelial cells, Kupffer cells, and stellate cells. Using the microfluidic chips, the authors confirmed the mechanism of action of several known hepatotoxic drugs and an experimental compound. A second experimental compound that induced fibrosis in rat Liver-Chips did not alter hepatocyte function in human chips, whereas a third compound demonstrated increased toxicity in dog Liver-Chips. Multispecies chips could help identify species-specific differences in drug metabolism and toxicity. Sci. Transl. Med. 11 , eaax5516 (2019).

Falla renal en el paciente con lesión medular aguda

Las lesiones medulares constituyen un evento catastrófico relacionado con discapacidades físicas significativas y grandesimplicaciones socioeconómicas. Entre sus complicaciones, la insuficiencia renal, se encuentra relacionada con mayor morbilidad y mortalidad. De todos los mecanismos fisiopatológicos propuestos de la enfermedad, destacan el desequilibrio en las funciones reguladoras del sistema nervioso autónomo, el estado inflamatorio sistémico producto de la activación exponencial de las células inflamatorias circulantes, y la rabdomiólisis producto del trauma. Estos cambios fisiológicos que llevan a la insuficiencia renal afectan el metabolismo de diferentes fármacos, en particular de aquellos con eliminación renal. Los componentes intracelulares de la maquinaria inflamatoria, incluidas enzimas y factores de transcripción, también pueden servir como dianas terapéuticas para resolver la inflamación en múltiples órganos posterior a una lesión medular.

Smoking Is Associated With Lower Dose-Corrected Serum Concentrations of Escitalopram.

Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers. A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram. Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers. Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.

Mapping human microbiome drug metabolism by gut bacteria and their genes.

Summary:Individuals vary widely in drug responses, which can be dangerous and expensive due to treatment delays and adverse effects. Growing evidence implicates the gut microbiome in this variability, however the molecular mechanisms remain largely unknown. We measured the ability of 76 diverse human gut bacteria to metabolize 271 oral drugs and found that many of these drugs are chemically modified by microbes. We combined high-throughput genetics with mass spectrometry to systematically identify drug-metabolizing microbial gene products. These microbiome-encoded enzymes can directly and significantly impact intestinal and systemic drug metabolism in mice and can explain drug-metabolizing activities of human gut bacteria and communities based on their genomic contents. These causal links between microbiota gene content and metabolic activities connect interpersonal microbiome variability to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.

Tools for Community-Based Pharmacist Patient Care Services to Support Optimal Opioid Use

Tools for Community-Based Pharmacist Patient Care Services to Support Optimal Opioid Use

An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials.

Species differences in drug metabolism and disposition can confound the extrapolation of in vivo PK data to man and also profoundly compromise drug efficacy studies owing to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active), and in differential activation of the transcription factors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), which regulate the expression of such enzymes as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug-efficacy testing and also patient-derived xenografts to predict individual patient responses to anticancer drugs. A number of humanized mouse models for cytochrome P450s, CAR, and PXR have been reported. However, the utility of these models has been compromised by the redundancy in P450 reactions across gene families, whereby the remaining murine P450s can metabolize the compounds being tested. To remove this confounding factor and create a mouse model that more closely reflects human pathways of drug disposition, we substituted 33 murine P450s from the major gene families involved in drug disposition, together with Car and Pxr, for human CAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A7. We also created a mouse line in which 34 P450s were deleted from the mouse genome. Using model compounds and anticancer drugs, we demonstrated how these mouse lines can be applied to predict drug-drug interactions in patients and discuss here their potential application in the more informed design of clinical trials and the personalized treatment of cancer.

Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2.

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

A Brief Outlook on Pharmacogenetics (PGx): Focus in MicroRNAs (miRNAs) and Cancer Stem Cells (CSCs)

It has been known that there are differences in response to medications both in terms of clinical activity and side effects. Among all influencing factors, genetic variation has been considered to play a crucial part. By genetic investigation, the differences in drug metabolism, transport and target could be disclosed. Termed as “pharmacogenetics (PGx)”, that focuses on the variants within one or more candidate genes. Genetic tests have been started for screening polymorphisms prior to drug prescription, moreover many biomarkers were developed in oncology. Recent PGx investigations have been conducted to identify mRNAs, microRNAs (miRNAs) and other downstream signals that are affected by variation in genes that might cause drug response variability. Another intriguing study related to PGx in cancer stem cells (CSCs) has recently aroused. CSC shows more resistant behavior to drug. CSCs are subpopulation of cells, which share some same markers with stem cells. CSC can induce specific signal transduction pathways. Variation in genes affect CSCs activity are generally neglected in the past PGx studies. This could be one of the explanation why past PGx studies in cancer cell do not achieve optimal clinical outcome. Keywords : pharmacogenetics, pharmacogenomics, microRNAs, cancer stem cells