Drug metabolism letters最新文献

Background: Methods to provide absolute quantitation of the administered drug and corresponding metabolites in tissue in a spatially resolved manner is a challenging but much needed capability in pharmaceutical research. Quantitative Whole-Body Autoradiography (QWBA) after a single- dose intravenous (3 mg/kg) and extravascular (30 mg/kg) administrations of an in vitro metabolically stable test compound (structure not reported here) indicated quick tissue distribution and excretion.

Objective: Good bioavailability and short in vivo half-lives were determined formerly for the same test compound. For closing gaps in the understanding of pharmacokinetic data and in vitro results, radioactive hot spots on whole-body tissue sections had been profiled.

Methods: Punches from selected tissue regions containing high radioactivity in the tissue sections previously analyzed by QWBA were extracted by a highly organic solvent and analyzed without any consecutive sample preparation step, applying Ultra High Performance Liquid Chromatography- Mass Spectrometry (UHPLC-MS) and off-line radioanalysis to maximize signal levels for metabolite identification and profiling.

Results: The analysis revealed that the test compound was metabolized intensively by phase I reactions in vivo and the metabolites formed were excreted in bile and urine. The predominant metabolites showed abundant signal intensities both by MS and by radioanalysis but the MS signal intensities generally underestimated the real abundances of metabolites relative to the unchanged drug.

Conclusion: This work illustrates that maximizing the sensitivity of tissue punch radioanalysis and the combination with UHPLC-MS leads to a better insight into pharmacokinetic processes by providing quantitative data with high molecular selectivity.

Background: Glutathione S-transferases (GSTs) are phase II metabolic enzymes crucial for the metabolism of electrophilic drugs. Additionally, several GST isoforms are involved in protein- protein interaction with mitogen-activated protein kinases (MAPKs), modulating apoptosis pathways.

Methods: To assess the potential change of enzymatic activity, we performed a GST enzyme assay with human recombinant GSTM1 in the presence and absence of MAPK8. Recently, GSTM1 has been demonstrated to interact with MAPK8 both in silico and in vitro. The binding interface predicted in silico comprised amino acid residues present on the surface of the protein and a few were deep in the active site of the protein.

Results: The experiment demonstrated that the GSTM1 activity was conserved even in the presence of MAPK8 in the assay.

Conclusion: The possible alteration in the activity of MAPK8 in this interaction needs to be evaluated in further experiments.

Background: Food-drug interactions may lead to suppression or induction of drug metabolizing enzymes. Pomegranate is a commonly used fruit in folk medicine all over the world. Data concerning the effect of pomegranate on the activity of UDP-glucuronosyltransferases (UGTs) is scarce.

Objective: The purpose of this work was to investigate the effect of pomegranate juice ingestion on the transcription of ugt2b1, ugt2a3, and ugt1a9 in the liver and small intestine of male mice.

Methods: Pomegranate juice was administered to 10 male mice for 14 days in drinking bottles instead of water. Ten control mice received water in the drinking bottles. On the 15th day, the mice were sacrificed and the liver and the small intestine were removed. The small intestine was divided into 3 parts. Total mRNA was extracted from samples of these specimens, and cDNA was synthesized by quantitative real-time polymerase chain reaction (RT-PCR) using specific primers for each ugt gene.

Results: The ugt1a9 mRNA level was reduced by 2.25-fold in the liver and by 6-, 1.5-, and 3-folds in the first, second and third part of the small intestine, respectively. The ugt2b1 mRNA level in the liver and the third part of the small intestine was not affected, while it was reduced by 3.7- and 3-folds in the first and second parts of the small intestine, respectively. The ugt2a3 mRNA level was not affected in the liver and the 3 parts of the small intestine.

Conclusion: Some ugt mRNA levels may be reduced by the ingestion of pomegranate juice, which may reduce the metabolism of their drug substrates. The consequences may be an accumulation of such drugs in the body and enhanced toxicity.

Background: CYP450 enzymes in the liver have a significant role in the metabolism of xenobiotics. Probe drug strategy is broadly used to evaluate the pharmacodynamic and pharmacokinetic drug/ herb-drug interactions/ food-drug interactions. Probe drugs reveal the exact pathway of drug metabolism in the liver by their targeted tractability property. The CYP3A4 isoenzyme metabolizes the majority of the drugs (65%).

Methods: The characteristics of targeted probe drugs were observed from the admetSAR (version2) online database.

Results: Midazolam is widely used as a probe drug because of its peculiar character. Midazolam affirms the accurate and consistent prediction of pharmacokinetic mediated drug interactions even in nanogram concentrations with or without a potent CYP3A inhibitor. Remarkably, midazolam is used as a CYP3A4 substrate in the majority of in vivo studies.

Conclusion: It is concluded that midazolam shows a good response in all clinical studies because of its lesser half-life and bioavailability when compared with other probe drugs.

Background: In the drug development process, an assessment of bioequivalence is an integral part. For the evaluation of generics against the comparator, average bioequivalence approach is the gold standard method. In the recent past, there were many discussions on whether we have the adequate tool to evaluate generics and thereby drug interchangeability (prescribability and switchability) issue is addressed as average bioequivalence approach just considers population mean. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches arise as different variances like inter/ intra-subject variance and subject- by-formulation variance along with population mean are considered.

Objective: Methoxsalen, in combination with long-wave UVA radiation, is used in the symptomatic management certain psoriasis. The study was aimed to establish the bioequivalence (BE) of a newly developed methoxsalen capsule (MTX test) with that of a reference methoxsalen capsule (MTX reference) using multiple BE methods (i.e., average [ABE], population [PBE], and individual [IBE]) by utilizing a new LC-MS/MS method.

Methods: This is an open-label, randomized, balanced, two-treatment, three-period, three-sequence, crossover, single-dose (20 mg, 2 × 10 mg capsules), comparative, oral BE study conducted in 52 healthy, adult males under fasting conditions. Along with various pharmacokinetic (PK) parameters ABE, PBE, and IBE were also determined in the single study.

Results: A non-compartmental model best described the concentration-time data of both MTX test and reference. Both the formulations demonstrated nearly similar values of BE parameters (i.e., AUCo-t, AUC0-∞, Cmax, Tmax, and t^1/2). For MTX test, the observed Cmax, AUC0-t, and AUC0- ∞ were 125.16±81.53 ng/mL, 313.73±260.86 ng h/mL, and 321.25±271.85 ng h/mL, respectively. For MTX reference, the values were 127.63±71.60 ng/mL, 329.11±252.91 ng h/mL, and 335.48±264.54 ng h/mL, respectively. The bioanalytical method was validated over the concentration range 0.100-100.00ng/mL and the coefficient of determination (r2) was ≥ 0.9991. The sensitivity of the method was 0.100 ng/mL with the accuracy and precision values of 115% and 10.54%, respectively.

Conclusion: A single dose of MTX test met the ABE criteria of 80.00% -125.00% for Cmax, AUCo- t, and AUC0-∞, against MTX reference. The study outcome by PBE and IBE approaches proved that MTX Test was bio-inequivalent to MTX reference. Using multiple BE assessment methods in a single BE study is a novel approach and may overcome shortcomings of conventional bioequivalence assessment methods.

The liver plays a crucial role in endogenous metabolic activity and homeostasis of macro and micronutrients. Further, it acts as a metabolic hub in mammals, where the ingested food-derived nutrients and xenobiotics or drugs are metabolized for utilization and/or excretion through its enzymatic and non-enzymatic machinery. Nutritional deficiency, one of the major public health problems, is associated with global disease burden, including pulmonary tuberculosis (PTB) caused by Mycobacterium tuberculosis (Mtb) infection. Though it is a curable and preventable infectious disease, millions of people succumb to death, and people in numbers larger than this are still suffering. This scenario is further complicated by the addition of new cases, disease recurrence, and the emergence of drug-resistant, all of which contribute to the spread of this epidemic. Though the manifestation of TB disease has multiple aetiologies, poor nutritional status and sub-optimal therapeutic concentrations of first-line anti-TB drugs are considered as potential contributors to its widespread prevalence. Among various factors, the pharmacokinetic variability of anti-TB drugs is one of the main causes for sub-optimal therapeutic drug concentration in TB patients, which is influenced by the host's genetic make-up and nutritional status, besides several others. However, the role of epigenetic changes in hepatic drug metabolic pathways and their transcript levels is largely unexplored. Therefore, in this review, an attempt has been made to understand the role of micronutrient deficiencies with special reference to fat-soluble vitamins, namely vitamin A, D, & E in pulmonary TB, their possible impact on epigenetic changes on the drug-metabolizing pathway genes, thus their expression levels and plausible influence on pharmacokinetic variability of anti-TB drugs, besides discussing the limitations and emerging potential opportunities. Eventually, this would help in developing the host-directed/personalized therapeutic strategies for the elimination of pulmonary tuberculosis (PTB).