Current Drug Metabolism - Volume 25, Issue 8, 2024

Cnidii Fructus (CF) is a herbal medicine with pharmacological activities such as antitumor, antiviral, antiallergic, antipruritic effects, and so on.

In this study, an ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was prepared and verified to measure the concentrations of seven analytes (bergapten, xanthotoxol, xanthotoxin, imperatorin, osthole, isopimpinellin, isoimperatorin) in HepG2 cells.

The separation of seven analytes was performed on an ACQUITY UPLC® BEH C18 column (2.1×100 mm, 1.7 μm) with a gradient mobile phase system of 0.1% formic acid/water and acetonitrile.

The CV of analytes was within 7.77%, and the bias was in the range of -5.43%-3.84%. The matrix effects of analytes ranged from 92.95% to 104.58%, and the extraction recoveries ranged from 76.45% to 104.69%. The relative standard deviation of stability results was less than 8.21%, indicating that seven analytes were stable.

The method was successfully applied to the determination of the content of seven analytes of CF extracts by UPLC-MS/MS, and the results will provide a reference for the cellular pharmacokinetics of CF.

Ferrets exhibit similar lung physiology to humans and display similar clinical signs following influenza infection, making them a valuable model for studying high susceptibility and infection patterns. However, the metabolic fate of several common human CYP450 probe substrates in ferrets is still unknown and has not been studied.

The purpose of this study was to investigate the metabolism of nine human CYP450 probe substrates in ferret hepatocytes and explore their metabolic rate differences between ferrets and other species.

Nine substrates were individually incubated in ferret hepatocytes for up to 120 min. At each time point, 30 µL mixtures were extracted for stability analysis using LC-MS/MS methods. After a 120-minute incubation period, 400 µL of the mixtures were extracted for metabolite identification using UHPLC-Q-Exactive Plus.

The metabolic clearance was determined as follows: testosterone > phenacetin > bupropion > omeprazole > midazolam > dextromethorphan > chlorzoxazone > taxol > diclofenac. Seven metabolites were identified from phenacetin. Deethylation was found to be the major pathway, and the major metabolite was matched with acetaminophen as probed with the CYP1A2 enzyme. Six metabolites were identified from diclofenac. Glucuronidation was the primary pathway, and a metabolite was found to match 4-OH-diclofenac as probed with the CYP2C9 enzyme. Twenty-two metabolites were identified from omeprazole. The major metabolic pathways included mono-oxygenation and sulfoxide to thioether conversion. No metabolite was found to match with 5-OH-omeprazole as probed with the CYP2C19 enzyme. Twenty-two metabolites were identified from dextromethorphan. Demethylation was found to be the major metabolic pathway, and one demethylation metabolite was matched with dextrorphan as probed with the CYP2D6 enzyme. Fourteen metabolites were identified from midazolam. Mono-oxygenation was found to be the primary metabolic pathway, and one of the mono-oxygenation metabolites was matched with 1-OH-midazolam as probed with the CYP3A4 enzyme. Eight metabolites were identified from testosterone. Mono-oxygenation and glucuronidation were identified as the major metabolic pathways. One mono-oxygenation was matched with 6-β-testosterone as probed with the CYP3A4 enzyme. Six metabolites were identified from taxol. Hydrolysis and mono-oxygenation were the top two metabolic pathways. No metabolite was matched with 6-α-OH-taxol as probed with the CYP2C8 enzyme. Ten metabolites were identified from bupropion. Mono-oxygenation and hydrogenation were identified as the top two metabolic pathways. No mono-oxygenation metabolite was matched with hydroxy-bupropion as probed with the CYP2B6 enzyme. Nine metabolites were identified from chlorzoxazone. Mono-oxygenation and sulfation were the top two metabolic pathways. One mono-oxygenation metabolite was matched with 6-OH-chlorzoxazone as probed with the CYP2E1 enzyme.

Nine human CYP probe substrates were clearly metabolized in ferret hepatocytes, demonstrating substrate-dependent metabolic rates in ferret hepatocytes and species-dependent metabolic rates in mouse, rat, dog, monkey, and human hepatocytes. Except for 6-a-5-OH-omeprazole, 6-α-OH-taxol, and hydroxy-bupropion, specific metabolites of other six probe substrates in ferret hepatocytes were detected and identified as probed with six human CYP enzymes, respectively.

To explore the relationship between oxidative stress biomarkers and the occurrence of acute kidney injury (AKI) alongside notable liver function disturbances in preterm neonates.

Given the immaturity of kidneys and incomplete liver development in preterm neonates, oxidative stress poses a considerable threat to their renal and hepatic health.

To find out the association between various oxidative stress biomarkers and polymorphisms of antioxidant enzymes with renal and live functions.

In this cross-sectional study, we gathered umbilical cord blood and peripheral blood samples for assessing oxidative stress biomarkers and identifying single nucleotide polymorphisms (SNPs) in antioxidant enzymes. Utilizing enzyme-linked immunosorbent assay kits, we quantified these oxidative stress biomarkers. Receiver-operating characteristics curve analysis was employed to ascertain the predictive capacity of these biomarkers, denoted by the area-under-the-curve (AUC).

Our findings revealed that umbilical cord heat-shock proteins emerged as robust predictors of neonatal AKI (AUC: 0.92; 95% CI: 0.8-1) with a defined cut-off concentration of 1.8 ng/mL. Likewise, umbilical cord 8-hydroxy-2-deoxy guanosine demonstrated significant predictability for liver function alterations (AUC: 0.7; 95% CI: 0.6-0.9) at a cut-off concentration of 2487.6 pg/mL.

We observed significant associations between SNPs in endothelial nitric oxide synthase and catalase with both AKI and impaired liver functions. Prospective studies are warranted to validate these findings, with a particular focus on exploring potential antioxidant interventions aimed at mitigating AKI and liver function abnormalities.

Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the hepatic enzymes CYP3A4/5 and efflux transporter P-gp, so drug-drug interactions may occur during their co-administration treatment. Therefore, this study aimed to evaluate the pharmacokinetic interaction between imatinib and tacrolimus in rats.

Rats were divided into groups I (30 mg/kg imatinib administered for 14 days), II (1.89 mg/kg tacrolimus and 30 mg/kg imatinib administered for 14 days), III (30mg/kg imatinib and 0.63mg/kg tacrolimus administered for 14 days), IV (1.89mg/kg tacrolimus for 14 days), and V (10mg/kg imatinib and 1.89mg/kg tacrolimus for 14 days). Blood samples were determined for whole blood of tacrolimus, plasma of imatinib, and N-desmethyl imatinib concentrations using ultra-performance liquid chromatography-mass spectrometry.

After 1 day of a single dose, tacrolimus had no significant effect on the pharmacokinetics of imatinib and N-desmethyl imatinib; imatinib significantly increased the AUC and Cmax of tacrolimus (P < 0.05). After 14 days of multiple doses, tacrolimus significantly reduced the AUC and Cmax of imatinib and N-desmethyl imatinib (P < 0.05). Further, imatinib significantly increased AUC0-24 and AUC0-∞ of tacrolimus (P < 0.05).

Imatinib increased tacrolimus blood concentrations after single and multiple administrations. Tacrolimus did not significantly affect the pharmacokinetics of imatinib after a single dose; however, tacrolimus might impact the absorption and metabolism of imatinib after multiple doses. The results showed that when imatinib and tacrolimus were co-administered, attention should be paid to the presence of drug-drug interactions.

This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects.

The trial followed a randomized, open-label, three-dose group design, enrolling 12 healthy participants and administering topiroxostat at three different dose levels. The study utilized NONMEM software for pharmacokinetic analysis, evaluating the impact of demographic and biochemical covariates on drug disposition.

Pharmacokinetic analysis shows the peak drug concentration (Cmax) under a single oral administration of 20, 40, and 80 mg of Topiroxostat, which was found in healthy subjects to be 215.46 ± 94.04 ng/mL, 473.74 ± 319.83 ng/mL and 1009.63 ± 585.98 ng/mL, respectively. The time to peak drug concentration (Tmax) was longer in females (0.79–0.98 h) than in males (0.53–0.93 h). Activated partial thromboplastin time (APTT) and triglycerides (TG) were included as covariates for the typical value of the absorption rate constant (TVKA) in our pharmacokinetic model. The dose (DOSE) was considered a covariate for the typical value of bioavailability (TVF1), and sex (SEX) was considered a covariate for the typical value of clearance (TVCL). The typical population values for topiroxostat included Q/F at 4.91 L/h, KA at 0.657 h-¹, Vc/F at 32.5 L, Vp/F at 30 L, and CL/F at 124 L/h.

The trial successfully established the pharmacokinetic parameters of topiroxostat in a Chinese population, confirming its safety and efficacy. The results support the need for individualized dosing strategies and optimize therapeutic outcomes.