Acknowledgements to reviewers
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations
Conclusion: Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Assessment of Inhibition of Bovine Hepatic Cytochrome P450 by 43 Commercial Bovine Medicines Using a Combination of In Vitro Assays and Pharmacokinetic Data from the Literature
Conclusion: This combination of in vitro assay and in vivo Cmax data provides a good approach to assess the inhibition of bovine medicines on bovine hepatic CYP450. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

The Effects of Special Patient Population Plasma on Pharmacokinetic Quantifications Using LC-MS/MS
Conclusion: Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH
Conclusion: Imatinib is not a substrate of OCTs 1-3 while the environmental pH modulates cellular disposition of imatinib. The observation that a slightly acidic extracellular pH influences imatinib cellular accumulation is important, considering the low extracellular pH reported in the hematopoietic leukemia/ cancer cell microenvironment. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Prominence of Oxidative Stress in the Management of Anti-tuberculosis Drugs Related Hepatotoxicity
Advanced medical services and treatments are available for treating Tuberculosis. Related prevalence has increased in recent times. Unfortunately, the continuous consumption of related drugs is also known for inducing hepatotoxicity which is a critical condition and cannot be overlooked. The present review article has focused on the pathways causing these toxicities and also the role of enzyme CYP2E1, hepatic glutathione, Nrf2-ARE signaling pathway, and Membrane Permeability Transition as possible targets which may help in preventing the hepatotoxicity induced by the drugs used in the treatment of tuberculosis. (Source: Dr...
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

A Practical Perspective on the Evaluation of Small Molecule CNS Penetration in Drug Discovery
The separation of the brain from blood by the blood-brain barrier and the bloodcerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting the central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrate that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS pene...
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Meet Our Editorial Board Member
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Acknowledgements to reviewers
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations
Conclusion: Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Assessment of Inhibition of Bovine Hepatic Cytochrome P450 by 43 Commercial Bovine Medicines Using a Combination of In Vitro Assays and Pharmacokinetic Data from the Literature
Conclusion: This combination of in vitro assay and in vivo Cmax data provides a good approach to assess the inhibition of bovine medicines on bovine hepatic CYP450. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

The Effects of Special Patient Population Plasma on Pharmacokinetic Quantifications Using LC-MS/MS
Conclusion: Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH
Conclusion: Imatinib is not a substrate of OCTs 1-3 while the environmental pH modulates cellular disposition of imatinib. The observation that a slightly acidic extracellular pH influences imatinib cellular accumulation is important, considering the low extracellular pH reported in the hematopoietic leukemia/ cancer cell microenvironment. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Prominence of Oxidative Stress in the Management of Anti-tuberculosis Drugs Related Hepatotoxicity
Advanced medical services and treatments are available for treating Tuberculosis. Related prevalence has increased in recent times. Unfortunately, the continuous consumption of related drugs is also known for inducing hepatotoxicity which is a critical condition and cannot be overlooked. The present review article has focused on the pathways causing these toxicities and also the role of enzyme CYP2E1, hepatic glutathione, Nrf2-ARE signaling pathway, and Membrane Permeability Transition as possible targets which may help in preventing the hepatotoxicity induced by the drugs used in the treatment of tuberculosis. (Source: Dr...
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

A Practical Perspective on the Evaluation of Small Molecule CNS Penetration in Drug Discovery
The separation of the brain from blood by the blood-brain barrier and the bloodcerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting the central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrate that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS pene...
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Meet Our Editorial Board Member
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Formation of a Toxic Quinoneimine Metabolite from Diclofenac: A Quantum Chemical Study
Conclusion: The results demonstrate the possibility of formation of quinoneimine metabolite due to various factors that are involved in the metabolism of diclofenac. The present study may provide the structural in-sights during the drug development processes to avoid the metabolism directed idiosyncratic toxicity. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Comparison of Rat and Human Pulmonary Metabolism Using Precision-cut Lung Slices (PCLS)
Conclusion: PCLS is a promising tool for the investigation of pulmonary drug metabolism. The data indicates that pulmonary CYP activity is relatively low and that there are significant differences in enzyme activity between rat and human lung. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

“Branched Tail” Oxyquinoline Inhibitors of HIF Prolyl Hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip
Conclusion: The optimized adaptaquin analogs are suitable for further preclinical trials. Activation of CYP2B6 with adaptaquin and its variants points to a potential increase in Tylenol toxicity if administered together. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study
Conclusion: Assuming that the radiotracer was proportional to total drug throughout a radiolabeled study was not valid in a 14C study in beagle dogs. This presumably resulted from unequal absorption of the radiotracer and nonradiolabeled test articles from the oral dose due to inequivalent solid forms. We were able to provide a more accurate description of the AME of GDC-0276 in dogs by characterizing the differential absorption of the radiotracer. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines
Conclusion: BUP and metabolites are not substrates of the major hepatic transporters tested and thus these hepatic transporters likely do not play a role in the overall disposition of the drug. Our results also suggest that caution should be taken when using the model CHO and HEK293 cell lines to evaluate potential roles of transporters in drug disposition. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Effect of Aqueous Extract of Azadirachta indica Leaves on Pharmacokineics and Pharmacodynamics of Glipizide
Conclusion: This indicated that the pharmacokinetics and pharmacodynamics of GZ altered by AZI might be due to the induction of CYP3A activity. In conclusion, AZI can decrease the bioavailability of GZ, and hence, it should be cautiously used. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Use of Cocktail Probe Drugs for Indexing Cytochrome P450 Enzymes in Clinical Pharmacology Studies – Review of Case Studies
Conclusion: The review provides a comprehensive list of various types of cocktail approaches and discusses some key considerations including the evolution of the cocktail approaches over time, perspectives and futuristic views for the use of probe drugs to aid the execution of clinical pharmacology studies and data interpretation. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Preface
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Meet Our Editorial Board Member
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Alam K et al. (2018) Drug Metabolism Letters; 12, 24-32.
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 23, 2018 Category: Drugs & Pharmacology Source Type: research

Quantitative Proteomics Reveals Changes in Transporter Protein Abundance in Liver, Kidney and Brain of Mice by Pregnancy
Conclusion: Protein abundance of drug transporters can be significantly changed particularly in the liver by pregnancy. These results will be helpful to understand pregnancy-induced changes in drug/xenobiotic disposition in the mouse model. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 23, 2018 Category: Drugs & Pharmacology Source Type: research

Genistein Affects Expression of Cytochrome P450 (CYP450) Genes in Hepatocellular Carcinoma (HEPG2/C3A) Cell Line
Conclusion: Our results suggest that treatment with genistein in non-toxic concentrations may impact the expression level of CYPs involved in the biotransformation of xenobiotics and drug metabolizing enzymes. Moreover, the downregulation of ATRA metabolism-related genes opens a new research path for the study of genistein as retinoic acid metabolism blocking agent for treating cancer and other pathologies. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 23, 2018 Category: Drugs & Pharmacology Source Type: research

A Novel In vitro Experimental System for the Evaluation of Enteric Drug Metabolism: Cofactor-Supplemented Permeabilized Cryopreserved Human Enterocytes (MetMax™ Cryopreserved Human Enterocytes)
Conclusion: Our results suggest that the MMHE system represents a convenient and robust in vitro experimental system for the evaluation of enteric drug metabolism. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 23, 2018 Category: Drugs & Pharmacology Source Type: research

Hepatic Flavin-containing Monooxygenase and Aldehyde Oxidase Activities in Male Domestic Pigs at Different Ages
Conclusion: Age impact on hepatic activities of both FMO and AO is obvious in domestic male pigs although age patterns of both enzymes are different. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 23, 2018 Category: Drugs & Pharmacology Source Type: research

Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities
Conclusion: Dual exposures to ethanol and NNK increase brain ethanol metabolism and inhibit the expression of CYP450s that regulate xenobiotic metabolism. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 23, 2018 Category: Drugs & Pharmacology Source Type: research

Acknowledgements to Reviewers
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 22, 2018 Category: Drugs & Pharmacology Source Type: research

In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone
Conclusion: Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 22, 2018 Category: Drugs & Pharmacology Source Type: research

Using LC Retention Times in Organic Structure Determination: Drug Metabolite Identification
Conclusion: In our experience, this simple methodology allows complementing the discovery efforts that saves resources for in-depth characterization using NMR. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 22, 2018 Category: Drugs & Pharmacology Source Type: research

New Perspectives on Acyl Glucuronide Risk Assessment in Drug Discovery: Investigation of In vitro Stability, In situ Reactivity, and Bioactivation
Conclusion: While the compounds tested from “withdrawn” and “warning category” all formed the glutathione adduct in buffer, none from “safe” category formed the glutathione adduct. In contrast, none of the compounds tested from any category formed methoxylamine conjugate, a reaction with putative aldehyde moiety formed via acyl migration. These results, highly favor the nucleophilic displacement as a cause of the reactivity rather than the acyl migration via aldehyde formation. The workflow presented could also be applied in the discovery setting to triage new chemical entities of intere...
Source: Drug Metabolism Letters - November 22, 2018 Category: Drugs & Pharmacology Source Type: research

Meet Our Editorial Board Member
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - November 22, 2018 Category: Drugs & Pharmacology Source Type: research

Evaluation of the Effect of Uremic Serum on Hepatic Reductase Functional Expression
Conclusion: Although uremic serum can upregulate mRNA expression of several reductases, this effect was not observed at the activity level. Future studies are necessary to improve our understanding of the mechanistic effects of impaired kidney function on drug reduction. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor
Conclusion: All in all, present findings would suggest that lumacaftor and ivacaftor-M6 are strong inducers of CYP3A4, potentially reducing ivacaftor concentrations; ivacaftor itself induces CYP3A4 to some extent. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Effect of CYP2D6 Poor Metabolizer Phenotype on Stereoselective Nebivolol Pharmacokinetics
Conclusion: The decline in plasma concentration of both nebivolol isomers in PM phenotypes, especially those with MR of 220 and 244, which indicate minimal or absent CYP2D6 activity, points to alternative mechanisms for nebivolol elimination. Collectively, our results are the first to show the significant impact of CYP2D6 PM phenotype on the metabolic disposition and in vivo exposure to both nebivolol isomers. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Evaluation of Herb-Drug Interaction of Synacinn™ and Individual Biomarker through Cytochrome 450 Inhibition Assay
Conclusion: Curcumin was found to be an active constituent that might contribute to the inhibition of SynacinnTM against CYP2C8, CYP2C9 and CYP2C19. It can be suggested that SynacinnTM can be consumed separately from a drug known to be metabolized by all tested CYP450 enzymes. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound
Conclusion: It was found that Nitroproston is rapidly hydrolyzed in rodent compared to human plasma incubations. Whereas Nitroproston is relatively stable in human plasma an enhanced hydrolytic activity was observed in whole human blood incubations. Extensive metabolism of Nitroproston in human whole blood was mainly associated with red blood cells. The observed interspecies variability highlights the need of suitable animal model selection for Nitroproston follow-up PK/PD studies. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS
Conclusion: Most of new metabolites via oxidative ring-opening and glutathionation were identified. Species differences in metabolism of 7-ethoxylcoumarin in hepatocytes were observed. The analysis of metabolites suggests that 7-ethoxylcoumarin may undergo 3,4-epoxidation responsible for formation of glutathione and its derived cysteine conjugates, carboxylic acid and its glucuronides, glucosides and sulfate. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Characterization of Liver- and Cancer-type-Organic Anion Transporting Polypeptide (OATP) 1B3 Messenger RNA Expression in Normal and Cancerous Human Tissues
Conclusion: Our findings are supportive of the potential role of Lt-OATP1B3 in cancer cells. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Cytochrome P450 1A2 Messenger RNA is a More Reliable Marker than Cytochrome P450 1A2 Activity, Phenacetin O-Deethylation, for Assessment of Induction Potential of Drug-Metabolizing Enzymes Using HepaRG Cells
Conclusion: The measurement of mRNA serves as a higher reliable indicator for the evaluation of CYP induction potential when using HepaRG cells. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Utility of Pooled Cryopreserved Human Enterocytes as an In vitro Model for Assessing Intestinal Clearance and Drug-Drug Interactions
Background: A recent advancement in isolation and cryopreservation has resulted in commercially available primary human enterocytes that express various drug metabolizing enzymes (DMEs) and transporters. The main objective of this study was to further evaluate the utility of pooled cryopreserved enterocytes, specifically MetMax™ cryopreserved human enterocytes (In vitro ADMET Laboratories), as an in vitro model for assessing intestinal clearance in comparison to hepatocytes. Methods: It was found that, for CYP3A4/5 substrates such as midazolam, amprenavir and loperamide, in vitro metabolic clearance is generally lowe...
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Preface
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Meet Our Editorial Board Member
(Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - August 28, 2018 Category: Drugs & Pharmacology Source Type: research

Genotoxicity of 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4] triazolo[4,3-a]pyrazine, a Potent H4 Receptor Antagonist for the Treatment of Allergy: Evidence of Glyoxal Intermediate Involvement
Conclusion: In the present investigation, a novel method was developed to trap glyoxal, which may potentially be liberated from piperazine moiety. These findings led to modifications on the piperazine ring to mitigate the bioactivation pathways leading to mutagenicity. Subsequently, the next generation compounds with modified piperazine moiety, retained H4R inhibitory potency in vitro and were not genotoxic in the Ames mutagenicity assay. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - February 8, 2018 Category: Drugs & Pharmacology Source Type: research

Evaluation of Farnesoid X Receptor Target Gene Induction in Human Hepatocytes: Amino Acid Conjugation
Conclusion: In conclusion, there appears to be some species differences in the activation of FXR target genes. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - February 8, 2018 Category: Drugs & Pharmacology Source Type: research

Transactivation Assays that Identify Indirect and Direct Activators of Human Pregnane X Receptor (PXR, NR1I2) and Constitutive Androstane Receptor (CAR, NR1I3)
Conclusion: Cell based transactivation assays employing the full-length receptors and native promoters identify both direct and indirect activators of either or both human PXR and CAR. (Source: Drug Metabolism Letters)
Source: Drug Metabolism Letters - February 8, 2018 Category: Drugs & Pharmacology Source Type: research