The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Mycophenolic acid (MPA) undergoes enterohepatic circulation (EHC) in the body and several population models have been proposed to describe this process using sparse data.• Recent studies in Whites have found that polymorphism in UGT1A9 could partly explain the large interindividual variability associated with the pharmacokinetics of MPA. WHAT THIS STUDY ADDS• A new population pharmacokinetic model for EHC combining MPA and its main glucuronide metabolite (MPAG) simultaneously was established based on physiological aspects of biliary excretion using intensive sampling data.• Pharmacokinetic profiles of MPA and MPAG with the UGT1A9 polymorphism in healthy Chinese were characterized. AIMSTo establish a population pharmacokinetic model that describes enterohepatic circulation (EHC) of mycophenolic acid (MPA) based on physiological considerations and to investigate the influence of polymorphisms of UGT1A9 on the pharmacokinetics of MPA. METHODSPharmacokinetic data were obtained from two comparative bioavailability studies of oral mycophenolic mofetil formulations. Nonlinear mixed effects modelling was employed to develop an EHC model including both MPA and its main glucuronide metabolite (MPAG) simultaneously. Demographic characteristics and UGT1A9 polymorphisms were screened as covariates. RESULTSIn total, 590 MPA and 589 MPAG concentration-time points from 42 healthy male volunteers were employed in this study. The chain compartment model included an intestinal compartment, a gallbladder compartment, a central and a peripheral compartment for MPA and a central compartment for MPAG. The typical population clearance (CL/F) estimates with its relative standard error for MPA and MPAG were 10.2 l h -1 (5.7%) and 1.38 l h -1 (6.9%), respectively. The amount of MPA recycled in the body was estimated to be 29.1% of the total amount absorbed. Covariate analysis showed that body weight was positively correlated with CL/F of MPA, intercompartment CL/F of MPA and distribution volume of MPA peripheral compartment. Polymorphisms of UGT1A9 did not show any effect on the pharmacokinetics of MPA and MPAG. The model evaluation tests indicated that the proposed model can describe the pharmacokinetic profiles of MPA and MPAG in healthy Chinese subjects. CONCLUSIONSThe proposed model may provide a valuable approach for planning future pharmacokinetic-pharmacodynamic studies and for designing proper dosage regimens of MPA.

A copper-catalyzed remote benzylic C−H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite siteselectivity, broad substrate scope, and wide utilizations of latestage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in twocomponent alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[f ][1,2]thiazepine 1,1-dioxides.

Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9‐targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 down‐regulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI‐73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti‐tumour efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer.