Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities.

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl4)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl4-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl4-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl4-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC50 values of 15.1 and 7.94 µM in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration.

Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite.

PURPOSE: To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS: The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS: After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 µM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS: The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.

Itraconazole and rifampicin, as CYP3A modulators but not P-gp modulators, affect the pharmacokinetics of almonertinib and active metabolite HAS-719 in healthy volunteers.

Almonertinib is a novel third-generation EGFR tyrosine kinase inhibitor. It is mainly metabolized by CYP3A in vitro, and N-desmethylated almonertinib (HAS-719) is the major active metabolite in human plasma. In this study, we investigated the effects of CYP3A inhibitor itraconazole and CYP3A inducer rifampicin on the pharmacokinetics of almonertinib and HAS-719 in 64 healthy volunteers. We found that when co-administered with itraconazole, the maximal plasma concentration (Cmax) and the plasma exposure (AUC0-t) of almonertinib were increased by 56.3% and 2.38-fold, respectively, whereas the Cmax and AUC0-t of HAS-719 were reduced by 86.8% and 71.8%, respectively. Co-administration with rifampicin reduced the Cmax and AUC0-t of almonertinib by 79.3% and 92.6%, but the AUC0-t of HAS-719 was unexpectedly decreased by 72.5%. In vitro assays showed that both almonertinib and HAS-719 were substrates of CYP3A and P-gp. Co-administration of rifampicin in Beagle dogs reduced the fecal recovery of almonertinib and HAS-719, and markedly increased the levels of metabolites derived from further metabolism of HAS-719, which was consistent with human plasma data, suggesting that although rifampicin was also a potent inducer of P-gp, the pharmacokinetic alternation of HAS-719 was mainly due to its further metabolism but not excretion changes. Moreover, we revealed that almonertinib was a moderately sensitive substrate of CYP3A in vivo. Special attention should be paid to the interaction between almonertinib and drugs or food affecting CYP3A activity in the clinical application of almonertinib.

Spontaneous Formation of Fluorescent Carbon Nanoparticles in Glutaraldehyde Solution and Their Fluorescence Mechanism.

Fluorescent carbon nanoparticles exhibit merits in terms of photochemical stability, functional modification flexibility and excellent biocompatibility. Currently, fluorescent carbon nanoparticles are often obtained by bottom-up or up-bottom strategies. So far, there has been no literature concerning spontaneous formation of fluorescent carbon nanoparticles. However, we have successfully found that fluorescent carbon nanoparticles can form spontaneously in the glutaraldehyde solution. Then further investigations were conducted on the storage time, pH and temperature, which could affect the fluorescence intensity of glutaraldehyde solution. The results indicate that the value of the fluorescence intensity will increase with the extension of the storage time. Moreover, the fluorescence mechanism of the glutaraldehyde solution was studied according to its properties and experiment results. Transmission electron microscopy was used to demonstrate nanoparticles in the glutaraldehyde solution. It's assumed that such phenomenon is probably attributed to the conjugated structure resulting from the polymerization of glutaraldehyde and the quantum confinement effect owing to the nanoparticles formed by the aggregation of polymers. Therefore, the spontaneous fluorescence produced by glutaraldehyde solution provides a simple and environmentally-friendly way to prepare fluorescent carbon nanoparticles.

Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients.

AIMS: Ningetinib is a tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (NSCLC). The present study aims to investigate the drug interaction of ningetinib and gefitinib and the mechanism of high plasma exposure of N-demethylated ningetinib (M1) in NSCLC patients. METHODS: Patients with NSCLC were recruited. Metabolism and transport assays were performed using in vitro models. Deuterated M1 was used to study the effects of ningetinib and gefitinib on M1 efflux in Institute of Cancer Research (ICR) mice. RESULTS: Upon co-administration of ningetinib with gefitinib, the plasma exposure of M1 was reduced by 80%, whereas that of ningetinib was not affected. In vitro experiments indicated that CYP1A1 was primarily responsible for M1 formation. Gefitinib was demonstrated to be a strong inhibitor of CYP1A1 with Ki value of 0.095 µM. M1 was identified as a substrate of efflux transporters P-gp and BCRP, while ningetinib and gefitinib were demonstrated to be their inhibitors, which was consistent with the results in mice. However, the inhibitory effect of gefitinib on efflux in vivo was negligible in the presence of ningetinib. CONCLUSION: The high plasma exposure of M1 in patients was attributed to the inhibition of M1 efflux by ningetinib and its low tissue affinity. When co-administered, gefitinib inhibited the formation of M1, but due to the low metabolic yield of M1 in vivo, the pharmacokinetics of ningetinib was not influenced. Inhibition of CYP1A1 may increase the concentration of ningetinib in target tissues, and the long-term safety and efficacy of ningetinib combined with gefitinib should be evaluated.