Objective: The objective of this study was to determine the intestinal and microbial disposition of flavonoids and how these disposition processes affect their enteric recycling. Design: Studies were performed using a perfused rat intestinal model or using enrichment cultures and a pure isolate of Enterococcus avium (LY1). Results: In the rat intestine, aglycones, such as quercetin and apigenin, were as permeable (P*eff ≥ 2) as compounds such as propranolol (100% absorption). However, a significant portion of the absorbed aglycones was conjugated and the metabolites were excreted into the lumen. Flavonoid glycosides, such as isoquercitrin and apigenin-7-O-glucoside, also had high apparent P*eff values (≥ 2) in the upper small intestine because of rapid hydrolysis. However, isoquercitrin was absorbed much slower (P*eff ≤ 0.7, p < 0.05) when hydrolysis was absent or inhibited by 20 mmol gluconolactone. Absorption of other intact glycosides was similar to intact isoquercitrin and was much slower than the corresponding aglycones (P*eff ≤ 0.7, p < 0.05). Intestinal bacteria, such as LY1, hydrolyzed the flavonoid glycosides used in the study. Excreted glycosidases were involved in the hydrolysis of glycosides because glycosides were poorly taken up by LY1. In conclusion, glycosidase-catalyzed hydrolysis is a critical first step in the intestinal and microbial disposition of flavonoid glycosides. Aglycones were not only rapidly absorbed, but also rapidly metabolized into phase II conjugates, which were then excreted back into the lumen. Therefore, intestinal and microbial glycosidases and intestinal phase II enzymes make a significant contribution to the disposition of flavonoids via the proposed enteric and enterohepatic recycling scheme.
Clinical data (n = 275) collected from 52 patients with respiratory tract infection receiving amikacin (AMK) by intravenous infusion were analysed with NONMEM, a computer program designed for estimating population pharmacokinetic parameters. Concentrations of AMK in serum were determined by fluorescence polarization immunoassay (FPIA). A two compartment open model was used for analysing AMK population pharmacokinetics. The influence of body weight (BW), creatinine clearance (CC), administration history (HIS) and state of pathology (chronic obstructional pulmonary disease, COPD) on pharmacokinetics was investigated. The pharmacokinetic parameters of AMK were shown to be influenced by creatinine clearance (CC) and COPD.
To develop a population pharmacokinetic (PK) model for cabazitaxel in patients with advanced solid tumors and examine the influence of demographic and baseline parameters.One hundred and seventy patients who received cabazitaxel (10-30 mg/m(2), 1-h IV infusion) every 7 or 21 days in five Phase I-III studies were analyzed by non-linear mixed-effect modeling (NONMEM VI). Model evaluation comprised non-parametric bootstrap and visual predictive checks.Cabazitaxel PK was best described by a linear three-compartment model with: first-order elimination; interindividual variability on clearance (CL), central volume of distribution (V1), and all intercompartmental rate constants except K21; interoccasion variability in CL and V1; proportional residual error of 27.8%. Cabazitaxel CL was related to body surface area (BSA) and tumor type (breast cancer; finding confounded by study). Typical CL for a non-breast cancer patient with a BSA of 1.84 m(2) was 48.5 L/h, with V1 26.0 L, steady-state volume of distribution 4,870 L and alpha, beta, and gamma half-lives of 4.4 min, 1.6, and 95 h, respectively. Sex, height, weight, age, Caucasian race, renal/hepatic function, and cytochrome P450 inducer use did not significantly further explain the PK of cabazitaxel. Bootstrap and posterior predictive checks confirmed the adequacy of the model.Cabazitaxel PK appears unaffected by most baseline patient factors, and the influence of BSA on CL is addressed in practice by BSA-dependent doses. This analysis suggests consistent cabazitaxel PK and exposure across most solid tumor types, although the potential influence of breast cancer on CL requires further confirmation.
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