The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (F_I) and liver (F_H) and the route of drug administration. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE).

Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer’s disease (AD). The kinetics of human Aβ40 (hAβ40) was examined in the rat pursuant to intravenous (IV) and intracerebroventricular (ICV) administration after pretreatment with calcitriol, the active vitamin D receptor ligand [6.4 nmol·kg-1 in 0.3 mL corn oil every other day for 4 intraperitoneal (IP) doses] to induce P-glycoprotein (P-gp) and enhance hAβ40 brain efflux. The interference of hAβ40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ40 plasma and CSF data after IV and ICV administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one CSF to four compartments. The model with only one CSF compartment (Model I) best fitted the IV data that showed a faster plasma decay t1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased brain efflux rate constants, k41 (1.8-fold) at the blood-brain barrier (BBB), when compared to the control group, as confirmed by the 2-fold (P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT An accurate description of hAβ40 that reflects the kinetic behavior of the toxic peptide is needed in defining it as a biomarker of Alzheimer’s disease. Modeling of hAβ40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflects faster peripheral distribution but slower equilibration between plasma and brain/CSF; with calcitriol pretreatment, which increased P-gp protein expression in brain, clearance was enhanced due to increased P-gp protein expression for hAβ40 efflux from brain.

Background: Tranexamic acid is an antifibrinolytic agent routinely used during hip and knee joint replacement surgery to minimize bleeding. Chronic kidney disease is a common chronic health problem seen among adults requiring major arthroplasty surgery. Tranexamic acid is renally cleared and may accumulate in chronic kidney disease. Optimal tranexamic acid dosing and dose adjustment for chronic kidney disease patients needing major arthroplasty is unknown. The objective of this study was to serially measure plasma tranexamic acid concentrations in patients with varied kidney function undergoing hip or knee replacement surgery for population pharmacokinetic modeling and to guide new dosing recommendations. Methods: A prospective cohort study enrolled 21 adults undergoing hip or knee replacement surgery between June 2020 and September 2022. Based on estimated glomerular filtration rate, the patients were stratified into good (greater than or equal to 60 ml · min⁻¹ · 1.73 m⁻²) and poor (less than 60 ml · min⁻¹ · 1.73 m⁻²) renal function. Serial blood samples were taken to measure plasma tranexamic acid concentration levels (primary outcome) after an intravenous tranexamic acid 20-mg/kg bolus dose after anesthesia induction. Secondary clinical outcomes included adverse events (thromboembolic events, seizures), red cell transfusion, mortality, and length of hospital stay. Analyses used curve stripping and population pharmacokinetic modeling and simulation. Results: Plasma tranexamic acid concentration levels were higher in patients with poor renal function and clearance compared to those with good renal function. Population pharmacokinetic modeling tested various tranexamic acid bolus and maintenance infusion regimens. Simulations revealed that single-bolus tranexamic acid administration leads to rapid rise and decline in plasma concentrations. This study identified that plasma tranexamic acid levels of 50 to 75 mg/l were maintained for approximately 4 h using a tranexamic acid bolus infusion of 15 mg/kg over a 15-min duration together with a maintenance infusion of 7.5 or 5 mg · kg⁻¹ · h⁻¹ for 2 h for the good and poor renal function groups, respectively. There was no difference in secondary outcomes. Conclusions: Population pharmacokinetic modeling and simulation resulted in recommendations for a new dosing regimen to optimize the antifibrinolytic effect of tranexamic acid and avoid excessive dosing.

The amyloid‐β (Aβ) peptides of 40 and 42 amino acids that are implicated in Alzheimer's disease may potentially aggregate into toxic oligomers and form neuritic plaques. The enzyme‐linked immunosorbent assay (ELISA) is a facile method used for the determination of Aβ concentrations in biological matrices, namely plasma, cerebrospinal fluid, and brain. The method is mostly used for the measurement of Aβ concentrations in transgenic mice, but it is unknown whether the ELISA method is suitable for measuring low, endogenous levels of Aβ in the brains of wild‐type mice. The Aβ ELISA kit manufacturer recommends use of 5 M guanidine hydrochloride (GuHCl), a protein‐denaturing agent, for homogenization of the brain tissue, followed by dilution back down to 0.1 M to avoid quenching by GuHCl. Components of brain matrices and GuHCl that could interfere with the quantitation have not been investigated. In this article, we describe an improved method involving homogenization of mouse brain with 1 M instead of 5 M GuHCl, reducing the dilution factor by 5× to provide a higher sensitivity. The modified ELISA assay is improved for the quantitation of brain Aβ peptides in wild‐type mice, where Aβ peptide levels are much lower than those in transgenic mouse models. © 2021 Wiley Periodicals LLC.This article was corrected on 4 August 2022. See the end of the full text for details.