Biopharmaceutics & Drug Disposition最新文献

To provide a theoretical basis for the rational use of cefditoren pivoxil in lactating women by conducting a pharmacokinetic study of cefditoren in the blood and milk of these women. Twelve participants meeting the inclusion criteria took cefditoren pivoxil tablets 200 mg after a meal, and the breast milk was collected over certain time periods with their volumes recorded. Blood samples were also collected at certain time points for pharmacokinetic analysis. Conduct a statistical analysis on the drug concentrations in breast milk and plasma and their correlation. Assessing the risk of taking cefditoren pivoxil during lactation using the milk-to-plasma ratio (M/P) and the relative infant dose (RID). Adverse events were monitored throughout the study period. Twelve lactating women participated in the study, providing a total of 84 breast milk samples. The correlation coefficient between cefditoren in breast milk and cefditoren in maternal plasma is 0.748 and is significant at the 0.01 level, with an M/P ratio of 0.008, and a RID of 0.0073%. Cefditoren is minimally distributed in human breast milk. There is a significant positive correlation between maternal blood drug levels and milk drug levels. Based on the M/P ratio and RID, it is inferred that the infant’s exposure is low, that is, the absolute dose of cefditoren transmitted to the infant through breastfeeding is low and is unlikely to cause any significant adverse effects. The results of this study will provide information for the use of cefditoren pivoxil in lactating women.

In the sphere of medical research, nanoencapsulated polymeric drugs in biological circumstances are an intriguing issue for therapeutical diagnosis. The nanoprecipitation approach was employed in this study to synthesis the nanoencapsulated polymeric scopoletin (NEP-Sc) and tested its effect against the HT-29 cell line (human colorectal adenocarcinoma cells). Further, the synthesized NEP-Sc was then characterized by ultra-visible spectroscopy (UV–Vis), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM) with energy dispersive X-ray analysis (EDAX), and dynamic light scattering (DLS) analysis. All the analysis confirmed the effective synthesis of NEP-Sc. The synthesized NEP-Sc was validated as anticancer drug through the conventional MTT assay, neutral red uptake assay, apoptosis assay using AO/EB and lactate dehydrogenase assay and trypan blue assay against HT-29 cells. The docking studies of scopoletin with multiple genes were also carried out using the PyRx—virtual screening tool. The findings indicated that increase in concentration of NEP-Sc exhibited dose dependent action of cell death against the HT-29 colon cancer cells. To summarize, the observed results of anticancer and computational modeling studies underscores the therapeutic potential of NEP-Sc in treating colon cancer.

Curcuminoids (CURs), natural polyphenols, are often combined with atorvastatin to treat hyperlipidemia. In order to assess the safety of combination, the effect of CURs on Cytochrome P450 (CYP) 3A2 activity in rats was investigated. Additionally, the effect of CURs on pharmacokinetics and pharmacodynamics of atorvastatin in rats was evaluated. The effect of CURs on CYP3A2 activity was studied using the probe drug method (dapsone as a probe drug). Pharmacokinetic parameters of atorvastatin with or without CURs were calculated to evaluate herb-drug interactions (HDIs). The effect of CURs on pharmacodynamics of atorvastatin was investigated by blood lipid, oxidative stress, aminotransferases, inflammatory factors and liver histopathology. C_max, AUC, and t_1/2 of dapsone in CURs group significantly increased (p < 0.05). C_max, AUC, and t_1/2 of atorvastatin in combination group significantly increased both in normal and hyperlipidemia rats (p < 0.01). Pharmacodynamics indexes of all treatment groups were significantly improved. There was no significant difference between AC group and combination group except HDL-C, SOD and liver index. In conclusion, CURs combined with atorvastatin could not effectively enhance the lipid-lowering effect or alleviate liver damage. However, CURs could inhibit CYP3A2 activity in rats and increase plasma exposure of atorvastatin, which might increase the risk of HDIs. The findings provided new insight into the combination of CURs and atorvastatin in treating hyperlipidemia.

Most cancer patients experience severe pain, and apatinib, a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, demonstrates therapeutic efficacy against gastric cancer. Ketamine, a psychotropic drug used for cancer pain relief, exhibits potential in inhibiting gastric cancer progression but is associated with dose-dependent adverse effects including neurological toxicity and dependency. Thus, clarifying whether apatinib influences ketamine therapy when co-administered is critical. In this study, we investigated apatinib's inhibitory effects on ketamine metabolism using CYP2C9 and CYP3A4 isoform assays. Results showed that apatinib exerted inhibition of ketamine metabolism, acted as a noncompetitive inhibitor of CYP2C9*1, CYP2C9*16, and rat liver microsomes (RLM), a competitive inhibitor of CYP2C9*3 and CYP2C9*13, and a mixed-model inhibitor of four CYP3A4 alleles (*1, *4, *18, and *23). Molecular docking revealed apatinib's stronger binding affinity (−10.4 kcal/mol) to CYP3A4*1 than ketamine (−6.9 kcal/mol). Consequently, co-administration may increase adverse risk in poor metabolizers (PMs), warranting in vivo validation of their therapeutic interaction.

Almonertinib has been approved for the first-line therapy of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). As a hepatoprotective agent, magnesium isoglycyrrhizinate (MgIG) was widely used in the treatment of drug-induced liver injury. Although Almonertinib is commonly prescribed in combination with MgIG in clinical application, the interaction research between them has not been reported. This research was conducted to explore the influences of MgIG on the pharmacokinetics of Almonertinib in rats and to investigate its possible molecular mechanisms. The plasma concentration of Almonertinib in male Sprague-Dawley (SD) rats was determined by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), the messenger RNA (mRNA) and protein expression levels of CYP3A1 (homologous to human CYP3A4) and P-glycoprotein (P-gp) in rat livers were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses. MgIG increased systemic exposure of Almonertinib significantly, resulting in increased AUC_0−t, AUC_0−∞, C_max, and t_1/2, and decreased CL_z. Furthermore, MgIG can markedly down-regulate the expression levels of CYP3A1 and P-gp in rat livers. There is a drug–drug interaction (DDI) between MgIG and almonertinib, which leads to an increase of systemic exposure for almonertinib. Meanwhile, CYP3A1 and P-gp in the liver may be the primary targets of mediating the DDI, but further clinical trials are needed to confirm these results.

Renal fibrosis, a critical contributor to chronic kidney disease, is characterized by interstitial expansion and excessive extracellular matrix accumulation. Due to their specificity, monoclonal antibodies (mAbs) and their fragments are promising candidates for treating renal fibrosis, but their distribution characteristics in fibrotic kidneys, particularly within the renal interstitium, remain unclear. This study investigated the tissue distribution of full-length IgG and Fab fragments in a unilateral ureteral obstruction (UUO)-induced renal fibrosis mouse model. Full-length IgG and Fab fragments were intravenously administered in UUO-induced renal fibrosis model mice. The concentrations in each organ and plasma were quantified using enzyme-linked immunoassay. In addition, the localization within the renal interstitium was evaluated by multiple techniques, including intravital and ex vivo confocal imaging under near-living conditions and the observation of the tissue sections via an in vivo cryotechnique. Both full-length IgG and Fab fragments showed higher distribution in fibrotic kidneys than in other organs. Specifically, Fab fragments had excellent selective accumulation in the fibrotic kidneys, whereas full-length IgG had higher absolute distribution due to slower plasma elimination. Imaging assessments revealed that both had widespread localization within the interstitial spaces of the fibrotic kidneys. Due to their superior selectivity for fibrotic kidneys, Fab fragments can be used to target fibrotic lesions. Due to its prolonged distribution, full-length IgG may offer advantages in sustained therapeutic effects. This study provides foundational insights into the distribution of mAbs and their fragments in fibrotic kidneys and underscores the importance of further pharmacokinetic analyses to refine antibody-based therapies.

Encorafenib is used to treat melanoma and colorectal tumors. Depression and gastric ulcer conditions can impact various physiological processes, including drug metabolism and pharmacokinetics. This study investigated the effect of a rat model of depression and gastric ulcers on the pharmacokinetics (PK) of encorafenib using the developed LC-QqQ-MS method. The chronic unpredictable mild stress (CUMS) model of depression and the indomethacin-induced gastric ulcer model were utilized to investigate the effect of depression and gastric ulcers on the pharmacokinetics of orally administered encorafenib. The focus was on parameters such as maximum plasma concentration (C_max), elimination half-life (t_1/2), mean residence time (MRT), volume of distribution (V_d), area under the curve (AUC), and apparent clearance (CL/F). Rats with depression exhibited a significant increase in maximum plasma concentration (C_max). In contrast, depression led to decreased t_1/2 and MRT, implying alterations in the drug's absorption and clearance. On the one hand, rats with gastric ulcers displayed a significant decrease in C_max, coupled with an extended time to reach maximum plasma concentration (T_max), prolonged t_1/2, MRT, and increased volume of distribution (Vd) of encorafenib. This preclinical study demonstrates that depression and gastric ulcers significantly impact the pharmacokinetics of encorafenib. These findings emphasize the importance of considering these disease conditions when designing encorafenib dosing regimens for optimal therapeutic outcomes in cancer patients.

The present study aimed to develop a novel colon-targeting microsphere of beclomethasone dipropionate (cMS/BDP) with enhanced pharmacological effect of BDP in the colon. cMS/BDP was prepared using Eudragit^® S-100 by the emulsion solvent diffusion method, and its physicochemical properties were characterized. A pharmacokinetic study was conducted to assess systemic exposure and colon distribution of BDP after oral administration of cMS/BDP to rats. A pharmacodynamic study was carried out to evaluate the anti-inflammatory effect of cMS/BDP after its oral administration to ulcerative colitis model rats. The particle size of cMS/BDP was calculated to be ca. 20 μm, and most BDP in cMS/BDP might be in an amorphous state. In dissolution tests, cMS/BDP showed pH-dependent release behavior of BDP and marked BDP release at pH 7.4. After oral administration of cMS/BDP (5 mg-BDP/kg) to rats, BDP was rapidly metabolized to beclomethasone 17-monopropionate (17-BMP, a BDP metabolite) in the gastrointestinal tract and liver, and relative oral bioavailability of 17-BMP in the cMS/BDP group was calculated to be ca. 4.8% compared with that in the BDP solution group. The tissue-to-plasma partition coefficient value, an index of colon distribution, for cMS/BDP was found to be 15-fold higher than that for BDP solution. In the cMS/BDP (50 μg/kg) group, colonic myeloperoxidase activity and hyperplasia of the submucosa were negligibly elevated. From these findings, the cMS approach for BDP would be a promising dosage option for strategic colon delivery, leading to an improved therapeutic potential of BDP with a wide safety margin.

Nonclinical trials are crucial for assessing pharmaceutical efficacy and safety prior to clinical trials. However, disparities in drug metabolism between humans and animals complicate extrapolating animal data to humans. Variability in drug-metabolizing enzymes, such as carboxylesterases (CESs), contributes to differences in drug kinetics. This study aimed to explore species disparities in CES substrate specificity among humans (hCES1), mice (mCES1), and cynomolgus monkeys (mfCES1) using diverse atorvastatin ester derivatives. This study measured hydrolysis rates of 30 atorvastatin derivatives. Metabolites were identified via HPLC with an internal standard, measuring rates per unit time and enzyme amount. Enzyme metabolic activity was compared using hydrolysis rates. The structure of the alkoxy group resulted in differences ranging from approximately half to 8.97-fold between hCES1 and mCES1 and differences ranging from similar to 15.82-fold between hCES1 and mfCES1. Caution is warranted when extrapolating animal data to humans, especially for esters with diverse structures. Our focus on the alkoxy group structure highlights its impact on hydrolysis rates. Further investigation into species differences among CES enzymes is essential for accurate translational research.

Sulfated steroids such as pregnenolone sulfate (PregS) are important for neuronal development and cognitive functions. Given the hydrophilic sulfate moiety, it is assumed that PregS requires an active transport mechanism to cross the blood–brain barrier (BBB). The human organic anion transporting polypeptide (OATP)2B1 has been previously shown to transport sulfated steroids and is therefore a proposed candidate for the transport of PregS. In this study, we aimed to investigate the role of OATP2B1 in the uptake of PregS in the brain. Tritium-labeled PregS was intravenously administered to humanized (SLCO2B1^+/+), knockout (rSlco2b1^−/−), and wildtype (WT) rats. Accumulation of the radiotracer was analyzed in rat brain, liver, small intestine, kidney, heart, and muscle. Moreover, transporter expression in brain microvessels was assessed through targeted proteomics and Western blot analysis. The involvement of hOATP2B1 in PregS transport across the BBB was further studied using a hBMEC-based in vitro BBB model. Our results indicated no significant difference in accumulation of the radiotracer among the different rat genotypes in the brain or in other tissues. In line with what we observed in the rat model, the subsequent in vitro study showed no involvement of hOATP2B1 in the transport of PregS. Taken together, our findings highlight the species-specific differences in transporter expression and suggest that OATP2B1 does not mediate PregS uptake across the BBB.