Xenobiotica最新文献

A four-compartment model is presented that simulates inorganic mercury [Hg(II)] pharmacokinetics in blood, tissue, and excreta over a 70 day period. Simulations are validated against data collected from five human subjects, and previously analyzed (Farris, F.F., A. Kaushal, and J.G. Strom. 2008. "Inorganic Mercury Pharmacokinetics in Man: A Two-Compartment Model." Toxicol Environ Chem. 90: 519-533). In the model, two compartments simulate Hg(II) in blood: one for mobile-Hg(II) and the other for immobile-Hg(II). Two corresponding compartments simulate Hg(II) in tissue. Mobile-Hg(II) represents Hg(II) available for transport across cell membranes. Immobile-Hg(II) represents Hg(II) that is not easily transported. Following dosing, blood total-Hg(II) drops rapidly in all subjects. Blood mobile-Hg(II) also drops rapidly with a concomitant rise in blood immobile-Hg(II). For four subjects, immobile-Hg(II) becomes the dominant Hg(II) species in blood by day 4. For subject five, mobile-Hg(II) remains dominant in blood for the study duration. Tissue mobile-Hg(II) declines rapidly for four of the subjects, with a simultaneous rapid rise in tissue immobile-Hg(II). In subject 5, tissue mobile-Hg(II) declines linearly, and immobile-Hg(II) accumulates slowly in tissue. For all subjects, tissue mobile-Hg(II) is the primary source of fecal Hg(II). The major source for Hg(II) excreted into the urine is immobile-Hg(II) from tissue.

1. Polymorphisms in genes related to drug-metabolizing genes may affect tacrolimus exposure. This study aimed to assess the influence of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus pharmacokinetics and outcomes in allogeneic hematopoietic stem cell transplantation (HSCT).2. 46 adult patients receiving oral tacrolimus at an initial dose of 0.03mg/kg/day for acute graft versus host disease (GVHD) prophylaxis after allogeneic HSCT were enrolled in this retrospective study. Genetic polymorphisms were detected in relation to concentration/dose (C/D) ratios of tacrolimus and the incidence of acute GVHD and acute kidney injury (AKI).3. The CYP3A5 *3/*3 genotype and co-administration of voriconazole were significantly associated with increased C/D ratios of tacrolimus (P < 0.05). NR1I2 8055CC present a significant higher tacrolimus C/D ratio compared with carriers of 8055CT and 8055TT genotypes in allogeneic HSCT recipients with the CYP3A5*1 allele (P = 0.033). Younger age and recipients with the CYP3A5*1 allele were significantly associated with higher incidence of II-IV acute GVHD post-transplantation.4. CYP3A5*3, NR1I2 8055 C > T, and concomitant use of voriconazole are important determinants affecting tacrolimus pharmacokinetics. Moreover, CYP3A5*1 allele and younger age are independent risk factors for II-IV acute GVHD in HSCT recipients.

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C₀) of venetoclax and the fluconazole C₀ were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C₀ values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC_0-24 and C₀ of venetoclax were not associated with fluconazole C₀; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C₀ and fluconazole C₀ (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C₀. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C₀ is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumours, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit.2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein.3. We characterised inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans.4. Inavolisib had a moderate permeability (1.9•10^-6cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model.5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.

Intramuscular (250 mg once weekly) or subcutaneous (275 mg once weekly) injections of 17-hydroxyprogesterone caproate (17-OHPC) has been utilised to prevent recurent spontaneous preterm birth in pregnant women with a short cervix or those with a prior preterm birth but its efficacy in these conditions has been questioned. It is unclear whether adequate concentrations of 17-OHPC reach the suspected target organs such as the cervix and uterus following either IM or SC administration.The objective of this study was to determine feasibility and safety of vaginal administration of 17-OHPC in adult female Sprague Dawley rats and female New Zealand rabbits.Gels containing 17-OHPC were administered intravaginally to rats and rabbits for 10 consecutive days. After the last dose, serial blood samples and terminal uterine and adipose tissue samples were collected. 17-OHPC concentrations were measured by LC-MS-MS.Tissue histology showed that intravaginal administration of 17-OHPC was safe. There was no renal or hepatic toxicity as measured by liver function and kidney function tests.Intravaginal administration of 17-OHPC resulted in low systemic plasma concentrations but substantially higher uterus and adipose tissue concentrations of 17-OHPC. Composition of the formulation affected the tissue distribution of 17-OHPC.Future studies warrant further evaluation of the effect and safety of daily intravaginal administration of 17-OHPC gel in pregnant animals.

The metabolism and disposition of zamicastat, a reversible dopamine β-hydroxylase (DβH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [¹⁴C]-zamicastat.Zamicastat was rapidly absorbed and widely distributed to peripheral tissues, with total radioactivity almost completely recovered 168 h post-dose. Its main route of excretion was via faeces, whilst urine and expired air had minor roles.Maximum plasma concentration of zamicastat-related radioactivity occurred in the first hours, remaining quantifiable up to 144 h. The unchanged zamicastat plasma peak was 2 h post-dose and declined to low levels over 24 h.Zamicastat metabolism occurs largely during the first 8 h with only one metabolite identified in the latest time-point (96 h), the isothiocyanic acid/thiocyanic acid (tautomeric forms). Zamicastat metabolic pathway involved multiple reactions comprising desulphurisation, oxidative desulphurisation, N-debenzylation followed by further oxidation or N-acetylation, and the unexpected multistep metabolic pathway leading to isothiocyanic acid/thiocyanic acid.

The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele.CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole.Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC₅₀ of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A).Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).

Benzophenone-3 (BP-3), commonly known as oxybenzone, is an organic compound that acts as a sunscreen, protecting the skin from UVA and UVB rays. Thus, the objective of this study was to investigate the effects of BP-3 on the liver and thyroid using morphological and biochemical approaches.Adult male zebrafish were randomly assigned to three groups, each with three repetitions (n = 10 per group) water control, solvent control (0.01% ethanol), and 1 μg/L of BP-3, using a static exposure system for 96 h. After the experiment, histopathological analyses of the liver and thyroid were performed, along with histochemical analyses (glycogen) and biochemical evaluations of the antioxidant enzymes superoxide dismutase (SOD) and Catalase (CAT).Exposure to BP-3 resulted in significant histopathological changes in the liver of Danio rerio, increasing the frequency of circulatory disturbances, progressive changes, inflammatory responses, and regressive changes. On the other hand, the thyroid gland did not show any morphological changes during exposure to BP-3, maintaining its typical structure with follicles. There was a significant increase in SOD activity, while CAT showed no changes after 96 h of exposure.The results obtained demonstrate that exposure to BP-3 causes significant morphophysiological changes in the liver of D. rerio, highlighting not only the negative impacts on the health of these organisms but also the ecotoxicological potential of the substance and its consequences for aquatic biota in contaminated environments.

Drug products meeting the dissolution specifications is crucial in order to ensure consistent clinical performance. However, in certain cases, wider dissolution specifications may be required based on product behaviour. While the justification of such wider specifications may be challenging from a regulatory context, approaches such as physiological-based biopharmaceutics modeling (PBBM) can be utilised for this purpose.Product DRL is a fixed-dose combination product consisting of immediate release (IR) and extended-release (ER) portions. For the ER portion, the dissolution specifications consisted of four time points, and a proposal was made to relax the specification at the 2h time point (from 50-70% to 45-67%) to reduce the batch failures at the commercial scale.To support the wider specification, a PBBM was developed and extensively validated with literature & in-house studies. Virtual bioequivalence was performed using the pivotal clinical study data.Virtual dissolution profiles for proposed wider specifications were generated using three different approaches. The incorporation of lower and upper dissolution profiles into the model indicated the absence of impact on in vivo performance thereby justifying the specifications.Regulatory acceptance of proposed specifications with PBBM indicated the significance of using modeling approaches to reduce repeated testing thereby facilitating faster approvals.