Pharmacokinetics of polymyxin B in different populations: a systematic review.

BACKGROUND AND OBJECTIVES: Despite being clinically utilized for the treatment of infections, the limited therapeutic range of polymyxin B (PMB), along with considerable interpatient variability in its pharmacokinetics and frequent occurrence of acute kidney injury, has significantly hindered its widespread utilization. Recent research on the population pharmacokinetics of PMB has provided valuable insights. This study aims to review relevant literature to establish a theoretical foundation for individualized clinical management. METHODS: Follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, Pop-PK studies of PMB were searched in PubMed and EMBASE database systems from the inception of the database until March 2023. RESULT: To date, a total of 22 population-based studies have been conducted, encompassing 756 subjects across six different countries. The recruited population in these studies consisted of critically infected individuals with multidrug-resistant bacteria, patients with varying renal functions, those with cystic fibrosis, kidney or lung transplant recipients, patients undergoing extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT), as well as individuals with obesity or pediatric populations. Among these studies, seven employed a one-compartmental model, with the range of typical clearance (CL) and volume (Vc) being 1.18-2.5L /h and 12.09-47.2 L, respectively. Fifteen studies employed a two-compartmental model, with the ranges of the clearance (CL) and volume of the central compartment (Vc), the volume of the peripheral compartment (Vp), and the intercompartment clearance (Q) were 1.27-8.65 L/h, 5.47-38.6 L, 4.52-174.69 L, and 1.34-24.3 L/h, respectively. Primary covariates identified in these studies included creatinine clearance and body weight, while other covariates considered were CRRT, albumin, age, and SOFA scores. Internal evaluation was conducted in 19 studies, with only one study being externally validated using an independent external dataset. CONCLUSION: We conclude that small sample sizes, lack of multicentre collaboration, and patient homogeneity are the primary reasons for the discrepancies in the results of the current studies. In addition, most of the studies limited in the internal evaluation, which confined the implementation of model-informed precision dosing strategies.

Ursolic acid attenuates cholestasis through NRF2-mediated regulation of UGT2B7 and BSEP/MRP2.

Ursolic acid (UA), a pentacyclic triterpenoid, exhibits various pharmacological actions, such as anti-inflammation, anti-tumor, anti-diabetes, heart protection, and liver protection. However, the role of nuclear factor E2-related factor 2 (NRF2)-mediated regulation of uridine diphosphate glucuronosyltransferase (UGT2B7) and bile salt export pump (BSEP)/multidrug resistance-associated protein 2 (MRP2) in UA against cholestatic liver injury has not been cleared. The purpose of this study is to explore the effect of UA on cholestatic liver injury and its potential mechanism. The results of the liver pathology sections and blood biochemical indices demonstrated that UA significantly attenuated the cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) in a dose-dependent manner. The mRNA and protein levels of UGT2B7 and BSEP/MRP2 were remarkably increased in the liver of ANIT rats and HepG2 cells pretreated with UA, but this activation was suppressed with NRF2 silenced. In conclusion, our findings demonstrate that UA prevents cholestasis, which may be associated with NRF2-mediated regulation of UGT2B7, BSEP/MRP2.

Determination of tamsulosin in plasma of healthy Chinese male subjects by a novel and simple LC-MS/MS method and its application to pharmacokinetic studies.

Tamsulosin, the first highly selective α1-adrenoceptor antagonist, is widely used for urination disorders caused by benign prostatic hyperplasia (BPH). The pharmacokinetics and safety of 0.2 mg tamsulosin hydrochloride sustained-release capsules were evaluated in 60 healthy Chinese male subjects under fasting and fed conditions in this study. A simple, sensitive, and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of tamsulosin in human plasma, which has been applied to pharmacokinetic study. The analyte and internal standard (tamsulosin-d5) were extracted by protein precipitation, and separated on a ZORBAX Eclipse XDB-C18 column (4.6 × 50 mm,1.8 µm; Agilent Tech) using a gradient elution with mobile phases methanol and 5 mM ammonium acetate. The linear range was 0.05-15.0 ng/mL. It showed good selectivity in normal, hyperlipidemic, and hemolyzed blank matrices. The CV (%) of intra-batch precision was <4.4% and the RE (%) of accuracy was in the range of -5.0%-6.7%; the CV (%) of inter-batch precision was <-5.8% and the RE (%) of accuracy was in the range of 1.2%-4.0%. The mean extraction recovery for the analyte was 102.1 ± 3.75% and for the IS was 102.2 ± 2.00%. Two formulations were considered bioequivalent under fasting and fed conditions, and the 90% confidence intervals for the geometric mean test/reference ratios were within the predetermined range of 80%-125%. A single oral dose of 0.2 mg tamsulosin hydrochloride sustained-release capsule was well-tolerated throughout the clinical trial, and no > Grade 1 adverse events (AEs) and serious AEs occurred during the trial.