Drug Metabolism and Pharmacokinetics药物代谢与药代动力学
Drug Metabolism and Pharmacokinetics(英文缩写 DRUG METAB PHARMACOK),ISSN 1347-4367,eISSN 1880-0920,中文译名:药物代谢与药代动力学 是一本学术期刊。本页汇总该期刊的最新影响因子、分区信息以及最新收录于 PubMed 的文献,帮助您快速了解期刊全貌。
发文量统计区间：2025-10-01 至 2026-09-30，按本站收录文献的发表日期统计。
期刊介绍
历年影响因子趋势
| JCR 数据年份 | 影响因子 | JCR 分区 |
|---|---|---|
| 2021 | 2.041 | Q4 |
| 2022 | 2.100 | Q4 |
| 2023 | 2.700 | Q2 |
| 2024 | 2.200 | Q3 |
| 2025 | 2.200 | Q3 |
Drug Metabolism and Pharmacokinetics 最新收录文献
-
1. Population pharmacokinetic analysis and exposure-response analysis of brexpiprazole in Japanese patients with agitation in Alzheimer's dementia.
PMID:日期:2026-07-16The efficacy and safety of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD) were demonstrated in Japanese study with 1 and 2 mg/day doses. The purpose of this study was to investigate need for dose adjustment in Japanese patients with AAD using population pharmacokinetics (PopPK) and exposure-response (ER) analysis, given that this population was older and renally impaired. First, using PopPK analysis, applicability of the previous PopPK model for Japanese healthy volunteers and patients with schizophrenia, established in a previous study, was confirmed to predict brexpiprazole concentrations in Japanese patients with AAD. Then, using exposure data from the PopPK model, ER analysis demonstrated that ER relationship was adequately described by sigmoid E model, although some parameters (EC and Hill) had RSEs >60%. Covariate analysis using PopPK model indicated that older age and/or reduced renal function were associated with increased exposure. However, these changes were considered to remain within the plateau region of ER relationship, suggesting limited clinical impact on efficacy. Therefore, brexpiprazole dose adjustment according to patient characteristics was not considered necessary in Japanese patients with AAD. Given the limited data and residual model instability in ER analysis, further investigation may be warranted to confirm the findings.
-
2. Characterization of unusual pyrazole ring-rearranged metabolites of DS-1971a specific to monkeys.
PMID:日期:2026-07-15We previously reported that various metabolites were detected in mice, monkeys, and humans after oral administration of radiolabeled DS-1971a. Among these metabolites, mono- (M6) and di-oxidized (M12 and M13) forms were recognized as being specific to monkeys. Here, we report the definitive structures and formation mechanisms of these metabolites to elucidate the monkey-specific metabolism of DS-1971a. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis indicated that mass fragments of standard compounds for M6, M12 and M13, which were biosynthesized by a microorganism, were identical to those of in vivo samples from monkeys, but their full structures could not be identified. Therefore, M6, M12, and M13 were additionally subjected to UV, nuclear magnetic resonance (NMR) and X-ray crystal structure analyses, revealing that these metabolites possess 4-hydroxy (M6), and 4-hydroxy and 5-oxo pyrazole ring moieties (M12 and M13). Notably, M12 and M13 were rearranged stereoisomers of each other. Incubation study with recombinant monkey cytochrome P450s (P450s) suggested that monkey CYP2C8 is responsible for producing not only M6 from DS-1971a but also M12 and M13, both of which are further oxidized metabolites of M6. These results demonstrate novel and unusual metabolism of the pyrazole ring moiety of DS-1971a via monkey CYP2C8-mediated oxidation and rearrangement.
-
3. Development of a method for vancomycin monitoring in interstitial fluid using a novel porous microneedle array patch.
PMID:日期:2026-06-30Interstitial fluid (ISF) is a promising alternative matrix for therapeutic drug monitoring; however, practical and quantitative ISF-based therapeutic drug monitoring has not been established. The aim of this study was to develop a method to quantify vancomycin concentrations in dermal ISF using novel porous poly(glycolic acid) (PGA) microneedles and characterize vancomycin pharmacokinetics in rat ISF by applying a sodium-based correction method to address evaporation-related variability in the ISF sampling volume. Porous PGA microneedles fabricated using a non-solvent-induced phase separation process passively absorbed ISF within a short insertion time (e.g., 5 min). Vancomycin extracted from MNs was quantified via LC-MS/MS, showing linearity over 0.5-100 μg/mL (R = 0.994), precision of <8%, and accuracy within 92-107%. Following intravenous vancomycin administration (30 mg/kg) to rats, ISF concentrations mirrored those in the plasma at the terminal elimination phase, indicating that ISF may serve as a surrogate for plasma kinetics. Sodium-based correction reduced the variability in ISF vancomycin concentrations and improved their correlation with plasma concentrations (R = 0.834) relative to weight-based method results. These findings indicate that ISF sampling using PGA-based porous microneedles, combined with sodium-based volume correction, provides a minimally invasive and quantitatively reliable platform for ISF-based therapeutic drug monitoring.
-
4. Development and validation of LC-MS-based bioanalytical methods for oligonucleotide therapeutics: points to consider.
PMID:日期:2026-06-19The analysis of oligonucleotide therapeutics, including antisense oligonucleotides and siRNAs, using existing bioanalytical methods presents unique analytical challenges owing to their distinctive physicochemical properties. Although the ICH M10 guideline provides general bioanalytical validation frameworks, specific considerations for oligonucleotide therapeutics remain undefined, highlighting an urgent need for targeted points to be considered. This white paper presents comprehensive recommendations developed through expert consensus and a literature review by the Japan Agency for Medical Research and Development research groups, addressing the critical technical challenges in liquid chromatography-mass spectrometry (LC-MS)-based bioanalytical methods for oligonucleotide therapeutics. It focuses on ion-pair reversed-phase LC-MS methodologies and emerging techniques, such as hybridization extraction, addressing key issues, including mobile phase stability and degradation, metal adsorption mitigation, carryover prevention, internal standard selection, and matrix effects unique to nucleic acids. The comprehensive coverage includes sample preparation strategies, chromatographic optimization, mass spectrometric detection approaches, and validation parameters adapted from ICH M10, with fit-for-purpose modifications on a case-by-case basis when conventional acceptance criteria cannot be applied. This white paper provides practical recommendations for the development and validation of analytical methods specific to oligonucleotide therapeutics, supports regulatory submissions, and promotes the international harmonization of bioanalytical standards in this rapidly expanding therapeutic modality.
-
5. A permeability assay adapted for the assessment of very poorly permeable compounds in the bRo5 space.
5. 一种适用于评估bRo5空间中渗透性非常差的化合物的渗透性测定PMID:日期:2026-06-02Poorly permeable compounds in the beyond rule of 5 (bRo5) space often demonstrate acceptor well concentrations below the lower limit of quantification or limited resolution between apparent permeability (P) values. To address the acceptor well concentration limitation and better resolve differences between poorly permeable molecules, a straightforward solution was proposed, extend the incubation time from 2-h to 24-h to enable acceptor well concentrations to achieve quantifiable values. MDCK cells with knock out of the endogenous canine Mdr1 gene (MDCK-KO) were seeded on 96-Tanswell plates and grown to confluence over three days at which point the 24-h assay was initiated. The longer incubation time enabled receiver compartment concentrations to exceed limits of quantification enabling P determination in a test set of approximately 30 molecules. The approximately 10-fold increase in incubation time enabled P value determination of up to an order of magnitude lower compared to a 2-h incubation. The assay demonstrates good reproducibility and resolution between poorly permeable compounds. In summary, a straightforward modification of a traditional Transwell permeability assay has produced an assay suitable for the measurement and resolution of very poorly permeable compounds.
-
6. A novel scaling approach for human pharmacokinetic prediction of antibody-drug conjugates using minimal nonclinical data: Integration of monkey PK and in vitro data.
PMID:日期:2026-05-28Antibody-drug conjugates (ADCs) have emerged as promising cancer therapeutics; however, predicting their pharmacokinetics (PK) in humans remains challenging, particularly during early development. Therefore, we aimed to develop a practical translational approach to estimate the human PK profiles of ADCs and their cytotoxic payloads using nonclinical data. PK data from nine FDA and PMDA approved ADCs were analyzed. Allometric scaling (exponent = 1.0) was applied to the PK parameters in monkeys to predict the clearance and volume of distribution in humans, which had a high accuracy (within two-fold of the observed clinical values). Subsequently, compartment models were constructed for four ADCs, and the payload release rate constant (k) was estimated by fitting the monkey ADC and payload concentration-time profiles. The estimated k values were then directly applied to simulate human payload concentration-time profiles. The predicted human payload exposures were mostly within three-fold of the clinical data, regardless of differences in the linker type. In conclusion, this study demonstrates the use of a simple, single species scaling method using direct antibody measurements for the robust prediction of ADC and payload PK in humans. Our approach provides novel and efficient dose selection and risk assessment with minimal preclinical data.
-
7. {"_":"K-EDTA anticoagulant suppresses calcium-dependent paraoxonase 1-mediated hydrolysis in human plasma stability assays.","sub":["2"]}
PMID:日期:2026-04-21Plasma stability assays are routinely applied in early drug discovery to evaluate enzymatic liability and to support lead optimization efforts. Although these assays are generally regarded as robust, the extent to which pre-analytical variables influence specific plasma hydrolase pathways has not been systematically examined. In this study, the impact of plasma anticoagulant selection on hydrolysis was investigated using procaine and pilocarpine as prototypical substrates of the serine hydrolase butyrylcholinesterase (BChE) and the calcium-dependent hydrolase paraoxonase 1 (PON1), respectively. Plasma stability was assessed in dipotassium ethylenediaminetetraacetic acid (K-EDTA) and lithium heparin plasma collected from the same donors. Procaine exhibited comparable stability across both plasma matrices, consistent with BChE-mediated hydrolysis. In contrast, pilocarpine underwent substantial hydrolysis in lithium heparin plasma but appeared stable in K-EDTA plasma. This effect is most consistent with calcium chelation by EDTA, as evidenced by complete suppression of PON1-mediated pilocarpine hydrolysis in lithium heparin plasma following exogenous EDTA supplementation. Collectively, these findings demonstrate that K-EDTA anticoagulation can selectively mask calcium-dependent PON1-mediated plasma hydrolytic pathways, leading to underestimation of plasma lability for susceptible compounds. Anticoagulant choice therefore represents an underappreciated determinant in plasma stability assessment, with direct implications for mechanistic interpretation of plasma-mediated clearance pathways during early DMPK evaluation.
-
8. {"_":"Role of the arachnoid mater organic anion and cation transporters in the clearance of prostaglandin D and metformin from the cerebrospinal fluid in rats.","sub":["2"]}
PMID:日期:2026-04-17The arachnoid mater-forming cells, which exhibit expressions of organic anion and cation transporters, as well as tight junction proteins, form the blood-arachnoid barrier. The purpose of the present study was to clarify the roles of the arachnoid mater transporters in the cerebrospinal fluid (CSF) clearance of prostaglandin D (PGD) and metformin by using an intracisternal administration method for evaluating arachnoid mater-mediated transport in rats. Global proteomics of rat leptomeninges showed the transporter expression of Slc22a6/Oat1, Slc22a8/Oat3, Slco2a1/Oatp2a1, Slc22a2/Oct2, and Slco2b1/Oatp2b1. The CSF clearance of PGD and metformin was greater than that of FITC-inulin, which is a marker of CSF bulk flow and parenchymal diffusion. The CSF elimination of PGD was significantly inhibited by p-aminohippuric acid, diclofenac (substrates/inhibitors of Slc22a6/Oat1 and Slc22a8/Oat3), and taurocholate (a broad substrate/inhibitor of Slco family transporters), whereas that of metformin was blocked by cimetidine, tetraethylammonium, and thiamine (substrates/inhibitors of Slc22a2/Oct2). The CSF-to-circulating blood transfer of metformin was inhibited by tetraethylammonium. These results suggested that the PGD clearance from the CSF most likely occurred via Slc22a6/Oat1, Slc22a8/Oat3, Slco2a1/Oatp2a1, and Slco2b1/Oatp2b1, while the metformin clearance was primarily mediated by Slc22a2/Oct2, in the arachnoid mater. These transporters would regulate the CSF concentrations of pharmacologically active substances and drugs.
-
9. Differences in reactive metabolite formation and cytochrome P450 binding between acetaminophen and its bicyclo[1.1.1]pentane bioisostere.
PMID:日期:2026-04-15Bicyclo[1.1.1]pentane (BCP) is widely used as a bioisostere of 1,4-disubstituted benzene to prevent oxidative metabolism of the benzene ring by cytochrome P450s (P450s). In this study, we investigated its effectiveness in reducing metabolism-dependent toxicity using acetaminophen (APAP) as a model compound, which causes hepatotoxicity by forming the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). In cultured rat hepatocytes, APAP markedly reduced intracellular glutathione levels, whereas N-{3-hydroxybicyclo[1.1.1]pentan-1-yl}acetamide (BCP-APAP), in which the benzene ring of APAP is replaced with BCP, had only a minor effect, suggesting that BCP-APAP does not form NAPQI-like reactive metabolites. We then investigated the interactions of these compounds with human CYP1A2, CYP2E1, and CYP3A4, the major P450s involved in NAPQI formation, using inhibition assays. While both compounds similarly inhibited CYP1A2 and CYP3A4, only APAP inhibited CYP2E1, suggesting that BCP-APAP does not bind to CYP2E1. Docking simulations with 3D crystal structures of these P450s revealed that both compounds can bind to CYP1A2 and CYP3A4 in a similar orientation for heme-mediated metabolism, whereas BCP-APAP did not adopt an APAP-like docking pose in CYP2E1. These findings indicate that replacing the benzene ring in APAP with BCP prevents the formation of reactive metabolites and may subtly alter P450 binding properties in an isoform-dependent manner.
-
10. Physiologically-based pharmacokinetic modeling of coproporphyrin I, an endogenous OATP1B substrate, in cynomolgus monkeys: Bridging the inhibitory effect of rifampicin to humans.
PMID:日期:2026-04-02Coproporphyrin I (CP-I), an endogenous substrate of OATP1B, is gaining attention as a biomarker for predicting drug-drug interactions (DDIs) mediated by hepatic organic anion transporting polypeptide 1B (OATP1B). Its application for bridging preclinical and clinical DDI predictions has been widely studied in cynomolgus monkeys. This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of CP-I in monkeys based on our human CP-I model. First, reported DDIs involving an OATP1B substrate pitavastatin and an OATP1B inhibitor rifampicin at several doses were simultaneously analyzed using PBPK coupled with a cluster Gauss-Newton method (CGNM), estimating the in vivo inhibition constant (K) in the cynomolgus monkeys. Considering substrate-dependent difference in K (CP-I vs. pitavastatin) examined in plated monkey hepatocytes, the in vivo K was converted to that for CP-I (K). A middle-out approach enabled simultaneous fitting using plasma CP-I and rifampicin. The synthesis rate and hepatic overall intrinsic clearance of CP-I were found to be identifiable by the CGNM. Both parameters were several-fold higher in monkeys than in humans, suggesting the difference in the DDI sensitivity. In conclusion, this study demonstrates that the integrated PBPK-CGNM approach enables quantitative assessment of OATP1B-mediated DDIs in preclinical species while accounting for interspecies differences.