Drug Metabolism and Pharmacokinetics最新文献

The second-generation antipsychotic blonanserin is a highly selective, full antagonist of dopamine D₂ and D₃ and serotonin 5-HT_2A receptors. It is currently prescribed for patients with schizophrenia in Japan. We aimed to develop a population pharmacokinetic model of oral blonanserin, including data from 12 to 77 years old patients, to assess the covariates that influence blonanserin pharmacokinetics and evaluate appropriate dosage regimens in adolescents versus adults. The population pharmacokinetic analysis was conducted using plasma concentrations in 132 Japanese adolescent and 135 adult patients with schizophrenia (including 20 older adults [≥65 years] patients), and 49 healthy adults. The blonanserin population pharmacokinetics was described using a two-compartment model with first-order absorption with lag time. Relative bioavailability decreased in fasted conditions and with concomitant CYP3A4 inducer use. Apparent clearance in older adult was lower than adult and adolescent. Simulation revealed similar plasma exposures between adolescents and adults and slightly larger in older adults. Bayesian estimates of apparent clearance suggested no effects of age in adolescents between 12 and 18 years old. Together, these results reveal the pharmacokinetic characteristics of blonanserin over a wide age range and support the appropriateness of the approved dosing regimen for adolescent patients with schizophrenia in Japan.

The previously reported Template system for the prediction of human CYP2B6-mediated reactions (Drug Metab Pharmacokinet 26 309-330, 2011) has been refined with the introduction of ideas of allowable width, Trigger-residue and the residue-initiated movement of ligands in the active site. The refined system also includes ideas of bi-molecule binding on Template. With the use of these ideas in common with other Template systems for human CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, and CYP3A4, 360 reactions of 261 distinct chemicals reported as CYP2B6 ligands were examined in the refined system. From their placements on the refined Template and rules for interaction modes, verifications of good and poor substrates, regio- and stereo-selectivities, and inhibitory interaction became faithfully available for these ligands, in which all the chemicals tested in the previous study were included. From the comparison of substrate specificities of human CYP2B6 and rat CYP2B1, size differences of one of the enzyme residues, Shelf, were suggested as a cause of their distinct catalyses. The refined CYP2B6-Template system will thus offer more reliable estimations of this human CYP catalyses toward ligands of diverse structures, together with their deciphering information to lead to judgments of metabolisms.

CPX-351 (NS-87; Vyxeos®) has a characteristic liposomal formulation and contains cytarabine and daunorubicin at a 5:1 molar ratio, which demonstrates synergistic activity in both in vitro and in vivo animal models. It has been approved in several countries for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Since there are very few Asian patients, especially Japanese adult and pediatric patients, only a small clinical study has been conducted in Japanese adult patients and no study in Japanese pediatric patients. Therefore, we need to continue collecting data to ensure efficacy, especially in Japan. The objectives of this study were to evaluate the exposure and efficacy of CPX-351 in adult and pediatric Japanese patients. For these purposes, population pharmacokinetic and exposure-response analysis was conducted based on the established model/analysis using non-Japanese data by incorporating the newly obtained results of a Japanese clinical trial. No significant differences in pharmacokinetic exposure and efficacy were observed between non-Japanese adult patients and Japanese adult or pediatric patients. This information supports CPX-351 as a treatment option for untreated Japanese t-AML/AML-MRC patients on the basis of efficacy and safety when referred to the evidence from non-Japanese subjects.

Areca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans. In the present study, an HPLC-UV bioanalytical method was developed to evaluate the hydrolytic kinetics and clearance rates of arecoline and guvacoline in human liver microsomes (HLM) and cytosol (HLC). The bioassay was capable of quantifying arecoline and guvacoline (and carboxylate metabolites arecaidine and guvacine, respectively) with good sensitivity, accuracy, and precision. Kinetics of arecoline and guvacoline hydrolysis best followed the Michaelis-Menten model. Apparent intrinsic clearance (Cl_{int.in vivo}) of arecoline was 57.8 ml/min/kg in HLM and 11.6 mL/min/kg in HLC, a 5-fold difference. Unexpectedly, guvacoline was dramatically less hydrolyzed than arecoline in both HLM and HLC, with Cl_{int.in vivo} estimates of 0.654 ml/min/kg and 0.466 ml/min/kg, respectively. These results demonstrate, for the first time, arecoline undergoes significant hydrolysis with high clearance rates in the liver. Furthermore, differential tissue metabolic rates and utilization of specific esterase inhibitors unequivocally demonstrated arecoline is a substrate for CES1 and not CES2.

Substance use disorders (SUDs) are complex mental health conditions involving a problematic pattern of substance use. Challenges remain in understanding its neural mechanisms, which are likely to lead to improved SUD treatments. Human brain organoids, brain-like 3D in vitro cultures derived from human stem cells, show unique potential in recapitulating the response of a developing human brain to substances. Here, we review the recent progress in understanding SUD using human brain organoid models focusing on neurodevelopmental perspectives. We first summarize the background of SUD in humans. Moreover, we introduce the development of various human brain organoid models and then discuss current progress and findings underlying the abuse of substances like nicotine, alcohol, and other addictive drugs using organoid models. Furthermore, we review efforts to develop organ chips and microphysiological systems to engineer better human brain organoids for advancing SUD studies. Lastly, we conclude by elaborating on the current challenges and future directions of SUD studies using human brain organoids.

A retrospective study and an animal study were conducted to investigate factors affecting the transdermal fentanyl dose to achieve adequate pain relief in patients switched from other opioids. In the retrospective study, patient factors were included as gender, age, body mass index (BMI), and serum albumin concentration. In obese (BMI ≥25) patients, the post-titration dose of transdermal fentanyl was significantly lower than in normal (BMI 18.5-25) patients despite the initial dose was the same. To support this unexpected finding, fentanyl was administered intravenously and transdermally to Zucker (fa/fa) rats as an obese model and Zucker (+/+) rats as a control. No difference in systemic clearance (CL_tot) after intravenous administration was observed between the two groups. However, transdermal bioavailability (F) and fentanyl release ratio from the formulation (F_a) were significantly increased in Zucker (fa/fa) rats compared to Zucker (+/+) rats. Skin availability (F_skin), calculated as F divided by F_a, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.