Drug metabolism letters最新文献

Background: Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Whether the influx organic cation transporter 1 (OCT1) encoded by the gene SLC221A1 is implicated in the cellular uptake of imatinib is still controversial. Besides, imatinib ionization state may be modulated by the hypoxic acidic surrounding extracellular microenvironment.

Objective: To determine the functional contribution of OCTs and extracellular pH on imatinib cellular disposition.

Methods: We measured imatinib uptake in two different models of selective OCTs drug transporter expression (transfected Xenopus laevis oocytes and OCT-expressing HEK293 human cells), incubated at pH 7.4 and 6, using specific mass spectrometry analysis.

Results: Imatinib cellular uptake occurred independently of OCT1- OCT2- or OCT3-mediated drug transport at pH 7.4. Uptake of the OCTs substrate tetraethylammonium in oocytes remained intact at pH 6, while the accumulation of imatinib in oocytes was 10-fold lower than at pH 7.4, irrespectively of OCTs expressions. In OCT1- and OCT2-HEK cells at pH 6, imatinib accumulation was reduced by 2- 3-fold regardless of OCTs expressions. Since 99.5% of imatinib at pH6 is under the cationic form, the reduced cellular accumulation of imatinib at such pH may be explained by the lower amount of uncharged imatinib remaining for passive diffusion across cellular membrane.

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.

Background: "Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection.

Objective: The aim of the study is to characterize the toxicity and metabolism of adaptaquin and its new improved analogs.

Method: Liver-on-a-chip technology with differentiated HepaRG cells followed by LC-MS detection of the studied compounds and metabolites of the P450 substrate-inhibitor panel for CYP2B6, CYP2C9, CYP2C19, and CYP3A4.

Results: The optimized adaptaquin analogs show no toxicity up to a 100-fold increased range over EC50. The drugs are metabolized by CYP3A4 and CYP2B6 as shown with the use of the cytochrome P450 substrate-inhibitor panel designed and optimized for preclinical evaluation of drugs' in vitro biotransformation on a 3D human histotypical cell model using "liver-on-a-chip" technology. Activation of CYP2B6 with the drugs tested has been observed. A scheme for adaptaquin oxidative conversion is proposed.

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.

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 penetration. Indeed, CCSF usually over-estimates Cu-brain for efflux substrates and it provides no additional value over Cu-plasma as the surrogate of Cu-brain for highly permeable non-efflux substrates. A strategy described here for the evaluation of CNS penetration is to use in vitro permeability, P-glycoprotein (Pgp) and breast cancer resistance protein efflux assays and Cu-brain/Cu-plasma in preclinical species. Cu-plasma should be used as the surrogate of Cu-brain for highly permeable non-efflux substrates with no evidence of impaired distribution into the brain. When drug penetration into the brain is impaired, we recommend using (total brain concentration * unbound fraction in the brain) as Cu-brain in preclinical species or Cu-plasma/in vitro Pgp efflux ratio if Pgp is the major limiting mechanism for brain penetration.

Background: Diclofenac is a non-steroidal antiinflammatory drug. It is predominantly metabolized by CYP2C9. 4'-hydroxydiclofenac and its quinoneimine are the metabolites of diclofenac. However, few numbers of serious cases of idiosyncratic hepatotoxicity due to diclofenac metabolism were reported. The formation of the quinoneimine metabolite was found to be responsible for this idiosyncratic toxicity. Quinoneimine is an over-oxidized metabolite of diclofenac.

Method: In this work, computational studies were conducted to detail the formation of a quinoneimine metabolite from diclofenac. Further, the idiosyncratic toxicity of quinoneimine due to its reactivity was also investigated by quantum chemical analysis.

Results & 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.

Background: Polypharmacy, that is, two (or more) drugs administered together, may cause chemical or pharmacological interactions. Such interactions may alter the effect of either agent, leading to decrease or increase effectiveness of the drugs, which may cause adverse effects. The co-intake of complementary and alternative medicines with therapeutic medicine are supposed to influence pharmacodynamics or pharmacokinetics of the latter.

Objective: This study was conducted to determine the interaction of glipizide (GZ) with an aqueous extract of Azadirachta indica (AZI) leaves.

Method: The pharmacokinetics and pharmacodynamics of glipizide was evaluated in High Fat diet (HFD) and streptozotocin induced diabetic Sprague-Dawley rats. Two doses of the AZI leaf extract (250 and 500 mg/kg) were administered alone or in combination with GZ (5 mg/kg) and serum glucose during oral glucose tolerance test, AST, ALT, and ALP levels were as estimated. In vitro CYP3A activity of AZI at 50 µg and 100 µg was assessed using liver microsomes.

Results: In the glucose tolerance test, AZI and GZ showed a hypoglycemic effect. However, the hypoglycemic effect was lower when AZI was administered in combination with GZ compared with GZ alone. AZI at 100 µg has shown significant potentiation of CYP3A activity. AZI (500 mg/kg) pretreatment significantly decreased AUC and increased Tmax to 8 h.

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.

Background: Although the liver is the primary organ of drug metabolism, the lungs also contain drug-metabolizing enzymes and may, therefore, contribute to the elimination of drugs. In this investigation, the Precision-cut Lung Slice (PCLS) technique was standardized with the aims of characterizing and comparing rat and human pulmonary drug metabolizing activity.

Method: Due to the limited availability of human lung tissue, standardization of the PCLS method was performed with rat lung tissue. Pulmonary enzymatic activity was found to vary significantly with rat age and rat strain. The Dynamic Organ Culture (DOC) system was superior to well-plates for tissue incubations, while oxygen supply appeared to have a limited impact within the 4h incubation period used here.

Results: The metabolism of a range of phase I and phase II probe substrates was assessed in rat and human lung preparations. Cytochrome P450 (CYP) activity was relatively low in both species, whereas phase II activity appeared to be more significant.

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.