Clin Pharmacol Ther
Department of Clinical Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Published: April 2022
Hepatic drug-metabolizing enzymes (DMEs) play critical roles in determining the pharmacokinetics and pharmacodynamics of numerous therapeutic agents. As such, noninvasive biomarkers capable of predicting DME expression in the liver have the potential to be used to personalize pharmacotherapy and improve drug treatment outcomes. In the present study, we quantified carboxylesterase 1 (CES1) protein concentrations in plasma samples collected during a methylphenidate pharmacokinetics study. CES1 is a prominent hepatic enzyme responsible for the metabolism of many medications containing small ester moieties, including methylphenidate. The results revealed a significant inverse correlation between plasma CES1 protein concentrations and the area under the concentration-time curves (AUCs) of plasma d-methylphenidate (P = 0.014, r = -0.617). In addition, when plasma CES1 protein levels were normalized to the plasma concentrations of 24 liver-enriched proteins to account for potential interindividual differences in hepatic protein release rate, the correlation was further improved (P = 0.003, r = -0.703), suggesting that plasma CES1 protein could explain ~ 50% of the variability in d-methylphenidate AUCs in the study participants. A physiologically-based pharmacokinetic modeling simulation revealed that the CES1-based individualized dosing strategy might significantly reduce d-methylphenidate exposure variability in pediatric patients relative to conventional trial and error fixed dosing regimens. This proof-of-concept study indicates that the plasma protein of a hepatic DME may serve as a biomarker for predicting its metabolic function and the pharmacokinetics of its substrate drugs.
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http://dx.doi.org/10.1002/cpt.2486 | DOI Listing |
Int J Pharm
January 2025
Drug Delivery and Disposition, KU Leuven, Gasthuisberg ON2, Herestraat 49 - box 921, 3000 Leuven, Belgium. Electronic address:
The widespread prevalence of colorectal cancer and its high mortality rate emphasize the urgent need for more effective therapies. When developing new drug products, a key aspect is ensuring that sufficiently high concentrations of the active drug are reached at the site of action. Drug transporters and drug-metabolizing enzymes can significantly influence the absorption and local accumulation of drugs in intestinal tissue.
View Article and Find Full Text PDFNeuro Endocrinol Lett
November 2024
2nd Department of Internal Medicine - Gastroenterology, University Hospital Hradec Kralove and Faculty of Medicine, Hradec Kralove, Charles University, Czech Republic.
Objectives: To determine whether selected single nucleotide polymorphisms (SNPs) of genes encoding proteins responsible for the activation, transport, or metabolism of dabigatran and apixaban might be associated with a risk of gastrointestinal bleeding in a cohort of adult patients treated with these drugs. No previous study has focused specifically on the association with gastrointestinal bleeding.
Materials And Methods: Ninety-one patients treated with dabigatran or apixaban were genotyped for selected polymorphisms.
J Adv Res
December 2024
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing 100191, China. Electronic address:
Introduction: Liver fibrosis is the common fate of NASH and poses a major health threat with very limited pharmacological treatments.
Objectives: This study aims to investigate the preventive effect of hinokitone (HO), an isolated compound from Agathis dammara, on NASH fibrosis and its underlying mechanism.
Methods: To investigate the effect of HO on NASH fibrosis, C57BL/6 mice were either fed a high-fat diet (HFD) in conjunction with intraperitoneal injection of CCl for 8 weeks or single CCl for 14 days to establish mouse liver fibrosis model, and HO was administered by gavage simultaneously.
Biofactors
December 2024
Department of Urology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Bladder cancer (BC) is the most common urinary tract malignancy. Identifying biomarkers that predict prognosis and immune function in patients with BC can enhance our understanding of its pathogenesis and provide valuable guidance for diagnosis and treatment. Our findings indicate that increased ITGB1 expression is associated with higher clinical grade and stage, establishing ITGB1 as an independent prognostic risk factor for BC.
View Article and Find Full Text PDFAutophagy
December 2024
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels.
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