European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objectives: Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.

Methods: In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.

Results: 7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10^-6 cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4 l/kg and the clearance was 4.0 ± 0.3 l/h/kg after IV administration. After oral dosing (5 mg/kg), a C_max of 28.5 ± 5.0 ng/ml and T_max of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.

Conclusions: This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.

Background and objective: Rotigotine, a dopamine agonist, is used to treat Parkinson's disease and restless leg syndrome, with transdermal patches being the primary delivery method in clinical practice. However, quantitative information on the in vivo pharmacokinetics of rotigotine across various dosage regimens via transdermal administration remains limited, and this has been identified as a significant barrier to achieving precision medicine. This study aims to develop a novel physiologically-based systematic pharmacokinetic model tailored to rotigotine transdermal drug delivery. Based on the model, we quantitatively predicted rotigotine distribution patterns in target tissues to assess its in vivo efficacy and safety and to interpret the pharmacokinetic variability in transdermal patches according to covariate reflection.

Methods: The data used to develop the quantitative model included clinical outcomes from single (2-8 mg/24 h) and multiple doses (0.5-8 mg/24 h) of rotigotine transdermal patches administered to healthy adults and patients with idiopathic Parkinson's disease or restless legs syndrome. The model was designed to represent whole-body physiological systems, incorporate liver and kidney clearance mechanisms, and account for the specific physicochemical properties influencing drug permeation and distribution across various tissues.

Results: The model developed in this study effectively quantified the pharmacokinetic profiles of transdermal rotigotine within an acceptable variability. After transdermal application, rotigotine delivery to the target tissue, the brain, occurred rapidly, and the tissue concentrations at steady-state were approximately 10-fold higher than those in plasma. Incorporating weight as a covariate showed that in underweight individuals, tissue exposure to rotigotine increased by 1.61-fold, with a mean half-life extension of 1.50-fold compared to that of the normal weight population.

Conclusion: The quantitative model proposed in this study serves as a foundational tool for advancing precision medicine, reliably characterizing the in vivo pharmacokinetics of rotigotine transdermal delivery across various doses and regimens.

The clinical pharmacology of antiretroviral therapy (ART) in critical care presents unique challenges due to the complex interplay between HIV infection, critical illness, and drug management. This comprehensive review examines the pharmacokinetic and pharmacodynamic considerations of antiretroviral drugs in critically ill patients, where altered absorption, distribution, metabolism, and excretion significantly impact drug effectiveness and safety. Critical illness can substantially modify drug pharmacokinetics through various mechanisms, including impaired gastrointestinal motility, fluid shifts, hypoalbuminemia, hepatic dysfunction, and altered renal function. These changes, combined with potential drug-drug interactions in the polypharmacy environment of intensive care units, necessitate careful consideration of dosing strategies and monitoring approaches. The review addresses specific challenges in various critical care scenarios, including management of ART in patients with organ dysfunction, during renal replacement therapy, and in special populations such as those with sepsis or acute respiratory distress syndrome. It also explores the role of therapeutic drug monitoring in optimizing antiretroviral therapy and managing drug toxicities in critical care settings. Emerging areas of research, including long-acting formulations, nanotechnology-based drug delivery systems, and personalized medicine approaches, are discussed as potential future directions for improving ART management in critical care. The review emphasizes the importance of a multidisciplinary approach involving critical care physicians, infectious disease specialists, and clinical pharmacists to optimize outcomes in this complex patient population. This review provides clinicians with practical guidance for managing ART in critically ill patients while highlighting areas requiring further research to enhance our understanding and improve patient care in this challenging setting.

Background and objective: A gonadotropin-releasing hormone (GnRH) agonist such as leuprolide is widely used to achieve sustained suppression of testosterone levels, which play a critical role in the treatment of prostate cancer. Recent advances in drug delivery systems have led to the development of long-acting depot formulations, such as the 6-month intramuscular (IM) leuprolide formulation, which aim to simplify dosing and improve convenience for both patients and healthcare providers. Exploring extended dosing intervals for such formulations represents a promising approach to further optimize treatment regimens, potentially balancing efficacy with patient-centered care. The objective was to evaluate the efficacy of various extended dosing regimens of the leuprolide 6-month IM depot formulation for prostate cancer treatment. The primary objective was to assess whether extended dosing intervals could maintain testosterone concentrations below the castrate threshold of < 0.5 ng/ml and < 0.2 ng/ml in over 90% of subjects, as outlined in regulatory criteria.

Methods: The study utilized a previously published pharmacokinetic/pharmacodynamic model to simulate the testosterone suppression profiles for different extended dosing regimens, including every 6 months (Q6M), 7 months (Q7M), 8 months (Q8M), 9 months (Q9M), 10 months (Q10M), 11 months (Q11M), and 12 months (Q12M). The simulations were carried out with 1000 virtual subjects. Sensitivity analyses were also conducted to account for variability in baseline testosterone levels and fraction of drug absorbed.

Results: The simulation results indicated that extending the dosing interval from Q6M to Q8M could ensure that over 90% of subjects maintain testosterone concentrations below 0.2 ng/ml. Similarly, extending the dosing interval to Q9M would keep testosterone concentrations below 0.5 ng/ml in over 90% of subjects. The sensitivity analyses confirmed that these extended dosing regimens consistently achieved and maintained target testosterone levels across various scenarios.

Conclusion: The findings support the feasibility of extending the dosing intervals for the leuprolide 6-month IM depot formulation beyond the label-recommended 6 months. Specifically, the Q8M and Q9M regimens emerged as viable candidates for further clinical evaluation, offering potential benefits in reducing injection frequency while maintaining therapeutic efficacy. Further clinical studies are necessary to confirm the long-term efficacy of these extended dosing regimens.

Background and objective: Total glucosides of paeony (TGP) capsules, tripterygium glycoside tablets (TGT), and celecoxib are commonly used drugs in clinical practice for the treatment of Rheumatoid arthritis (RA). An UPLC-MS/MS method for the analysis of celecoxib in beagle dogs was developed, the herb-drug interactions (HDIs) between TGP and TGT with celecoxib were studied based on pharmacokinetics.

Methods: The method of acetonitrile precipitation was applied to process plasma samples. Celecoxib and furosemide (internal standard, IS) was separated by gradient elution, and detected using multiple reaction monitoring mode under the positive ion. The ion reactions used for quantitative analysis were m/z 379.82 → 315.82 for celecoxib, and m/z 328.74 → 204.88 for IS. HDIs experiments adopt a three-stage experimental design. In the first period, six beagle dogs was orally administered 6.67 mg/kg celecoxib. In the second period, TGP 20 mg/kg was given orally twice a day for 7 consecutive days, then celecoxib was orally administered. And, in the third period, TGT 1.5 mg/kg was orally given, twice a day for 7 consecutive days, then celecoxib was orally administered. The concentration of celecoxib in the three periods was detected, and HDIs were evaluated based on pharmacokinetics.

Results: Celecoxib exhibited good linearity in the range of 10-2000 ng/mL. The accuracy, precision, recoveries, matrix effects, and stability all met the standards. When celecoxib was used in combination with TGPC or TGT, the main pharmacokinetic parameters of celecoxib changed, C_max, AUC_(0-t) and AUC_(0-∞) increased, t_½ was prolonged, and CL and V_d decreased.

Conclusion: A novel UPLC-MS/MS approach was successfully performed and applied to measure celecoxib in beagle dog plasma. TGP and TGT could inhibit the metabolism of celecoxib in beagle dogs, thereby affecting the pharmacokinetic parameters of celecoxib and increasing plasma exposure to celecoxib.

Objective: The objective of this study was to determine the apparent intrinsic clearance (Cl_{int, app}) and fraction unbound in human liver microsomes (f_{u, mic}) of 86 marketed central nervous system (CNS) drugs and to predict the in vivo hepatic blood clearance (CL_{h, b}).

Methods: Cl_{int, app} in human liver microsomes (HLM) was determined by substrate depletion, and f_{u, mic} was determined by equilibrium dialysis. The relationship between lipophilicity (logP) and unbound intrinsic clearance (Cl_{int, u}) was explored using the Biopharmaceutical Drug Disposition Classification System (BDDCS) and Extended Clearance Classification System (ECCS). The predicted hepatic blood clearance by direct scaling, conventional method and Poulin method using well-stirred (WS) and parallel-tube (PT) models were compared with observed values.

Results: The Cl_{int, app} in HLM ranged from < 5.8 to 477 µl/min/mg. The f_{u, mic} in HLM ranged from 0.02 to 1.0. The scaled Cl_int values ranged from < 5 to 4496 ml/min/kg. The metabolic rate increased with an increase in logP (logP ≥ 2.5) of the CNS compounds. The direct scaling and Poulin methods showed comparable results based on the percentage of clearance predictions within a two-fold error. The conventional method resulted in under-predictions of Cl_{int, in vivo} or CL_{h, b} using the WS or PT models. The Poulin method is favored over the other methods based on the statistical parameters.

Conclusions: Experimental Cl_{int, app} and f_{u, mic} for 86 CNS compounds were successfully determined, and the scaled clearance was used to predict the hepatic blood clearance of 34 drugs. The success of prospective clearance predictions using HLM is expected to be high for most of the lipophilic BDDCS class 1 and class 2 and ECCS class 2 CNS compounds. The Poulin method resulted in more accurate predictions falling within a two-fold error of the observed values using the WS or PT models.

Background and objective: Atorvastatin is dosed in its active acid form although it exists in equilibrium with its inactive lactone form in vivo. Although in vitro atorvastatin acid displays pH-dependent conversion to the lactone metabolite, pharmacokinetic (PK) data on the effect of elevated gastric pH on atorvastatin and major atorvastatin-related species are not currently available. In this dedicated study, we investigated the effect of food and acid-reducing agents on the PK of atorvastatin and its three major metabolites in humans.

Methods: This was an open label, randomized, crossover study conducted in 17 healthy volunteers. Part 1 examined the PK of a 10-mg dose of atorvastatin co-administered with or without a 600-mg dose of sodium bicarbonate in fasted and fed states. Part 2 was a single assessment to examine the PK of a 10-mg dose of atorvastatin in the fasted state following a 5-day treatment course of 40-mg daily esomeprazole. Gastric pH was monitored during treatments using Heidelberg capsules. A linear mixed effects model was used to derive ratios for PK parameters of atorvastatin and metabolites between treatments.

Results: Similar to previous food effect studies, food significantly decreased the maximum concentration (C_max) and increased the time to C_max (t_max) of atorvastatin, with minimal effect on total exposure of atorvastatin or metabolites. Neither sodium bicarbonate, in the fed or fasted state, nor treatment with esomeprazole had a clinically meaningful effect on the exposure of atorvastatin or its metabolites.

Conclusions: According to these results, atorvastatin PK does not appear to be sensitive to changes in gastric pH.

Background and objectives: As an immunosuppressant, mycophenolate mofetil (MMF) is used to prevent graft versus host disease (GVHD) in patients after hematopoietic stem cell transplantation (HCT). This study aimed to establish a population pharmacokinetic model and simulate the dosage protocol in HCT patients with thalassemia (TM) to fill the gap of lacking MMF dosing regimen.

Methods: The mycophenolic acid (MPA) plasma concentrations were obtained from HCT patients with TM after using MMF. The population pharmacokinetic (PPK) parameters were obtained by NONMEM (Version VII, Level 2.0; ICON Development Solutions, Ellicott City, MD, USA) program. Monte Carlo simulations were used to determine the optimal dosing.

Results: A total of 239 blood samples from 31 pediatric patients were available, the PPK of MPA was described as a two-compartment model. The typical values for MPA clearance (CL), central distribution volume (V₂), peripheral distribution volume (V₃), intercompartmental clearance (Q), and absorption rate constant (Ka) were 14.9 L/h, 83.5L, 141L, 3.13 L/h, and 1.37/h respectively. The inter-individual variability (IIV) of CL and V₂ were 35% and 41%, respectively. Simulation results suggested that, as the patient's body surface area (BSA) value increased, MMF dosage initiated from 500 mg twice daily was effective.

Conclusions: A 'tiered' dosage regimen including patient urea and with doses stratified across BSA quartiles, rather than a 'one dose fits all' regimen, would help individualize MMF therapy in this population.

Background and objectives: Hypertensive nephropathy (HN) has become one of the main causes of end-stage renal disease. Drug combination therapy is a common clinical treatment for HN. However, the impact of HN on drug-metabolizing enzymes and transporters, which may lead to drug-drug interactions (DDIs) and even trigger toxic side effects, remains unclear. The aim of this study was to investigate changes in major drug-metabolizing enzymes and transporters in the liver and kidney of HN rats to improve the scientific foundations for the clinical treatment of HN.

Methods: Spontaneously hypertensive rats (SHRs) were used as an animal HN model because their hypertension is similar to that of humans. Wistar-Kyoto rats (WKYs) were used as the control group. Body weight, blood pressure, hematoxylin-eosin (HE) staining and biochemical analysis were performed to evaluate whether the HN model was successfully constructed. Quantitative real-time polymerase chain reaction (PCR) and western blotting were used to evaluate the mRNA and protein expression of drug-metabolizing enzymes, transporters and related nuclear transcription factors.

Results: In HN rats, the mRNA expression of the drug-metabolizing enzymes cytochrome P450 (Cyp) 2b1, Cyp2c11, Cyp3a1 and Cyp7a1 was significantly upregulated. The protein level of CYP3A1 was consistent with its mRNA expression. Interestingly, the mRNA expression of the hepatic transporters organic cation transporter (Oct) 1, Oct2, organic anion transporter (Oat) 1, Oat2, multidrug resistant protein (Mrp) 2, multidrug resistance (Mdr) 1, organic anion transporting polypeptide (Oatp) 1b2 and na+/taurocholate cotransporting polypeptide (Ntcp) was also markedly upregulated. This may be directly influenced by the upregulation of the expression of the nuclear receptors farnesoid X receptor (Fxr), pregnane X receptor (Pxr), liver X-activated receptor (Lxr) and constitutive androstane receptor (Car). In the kidney of HN rats, the mRNA level of the drug-metabolizing enzyme Cyp2b1 significantly increased, while levels of Cyp1a1, Cyp2c11, Cyp3a1 and Cyp3a2 did not significantly change. The mRNA expression of the transporters multidrug and toxin extrusion (Mate) 1 and Mrp2 was obviously increased but was markedly depressed for peptide transporters (Pept) 1 and Pept2. These changes may be related to the cross effects of Pxr, Fxr and Car in kidney.

Conclusion: HN pathological status can alter the expression of drug-metabolizing enzymes and transporters in the liver and kidney to varying degrees, thus affecting the disposition of substrate drugs in vivo. This suggests that to avoid potential risks, caution should be exercised when administering combination therapy for HN treatment.