European Journal of Drug Metabolism and Pharmacokinetics最新文献

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.

Background and objective: Neonatal pharmacotherapy has gained attention from clinicians and regulatory agencies for optimizing the dosage of the drug which improves therapeutic outcomes in this special population. Piperacillin-tazobactam antibiotic is commonly used as a therapeutic option for treatment of severe infection in neonatal intensive care units. There are few population pharmacokinetic (PopPK) studies of piperacillin and tazobactam published for this specific population and which were not validated in other study settings. The aim of this study was to externally evaluate the published population pharmacokinetic models for piperacillin-tazobactam.

Methods: A systematic review was conducted through Scopus, PubMed, and Embase databases to identify PopPK models. Clinical data collected in neonates treated with piperacillin-tazobactam were used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions.

Results: Three PopPK models were identified for external evaluation. A total of 53 plasma samples were collected from 46 neonates admitted in the neonatal intensive care unit. The PopPK models reported by Cohen-Wolkowiez et al. for piperacillin and Li et al. for tazobactam were able to predict well for our clinical data.

Conclusion: The PopPK models by Cohen-Wolkowiez et al. and Li et al. predicted our data well for piperacillin and tazobactam with the lower relative median absolute predictive error (rMAPE) of 8.61% and 16.48% and relative root mean square error (rRMSE) of 0.01 and 0.03, respectively. External evaluation of the published PopPK models of piperacillin and tazobactam resulted in enhancing their credibility to be implemented in clinical practice.

Background and objective: Cyclosporin A (CsA) exhibits a narrow therapeutic index and large inter-individual variation in pharmacokinetics. Two intermittent and 24-h continuous infusions (CI) are both commonly used regimens in hematopoietic stem cell transplantation (HSCT), with no universal consensus. The objective of this study was to assess whether CsA as a 2-h, twice-daily intravenous infusion (2 h/12 h) is non-inferior to 22 h CI every 24 h (22 h-CI/24 h) in terms of acute graft-versus-host disease (aGVHD) incidence and adverse events in allogeneic HSCT adult patients.

Methods: An open-label randomized trial recruited 31 allogeneic HSCT patients to receive the 2 h/12 h or 22 h-CI/24 h regimen. The primary outcomes were the incidence of aGVHD and CsA-related adverse events. The secondary outcomes included the correlation between the time concentration and area under the concentration-time curve (AUC) of 2 h/12 h versus 22 h-CI/24 h regimens.

Results: Six (19.4%) patients developed aGVHD. There was no statistically significant difference between the two groups concerning the incidence of aGVHD (13.3% in 2 h/12 h vs. 25% in 22 h-CI/24 h; p = 0.359). The distribution of different aGVHD types (p = 0.20) and mortality (p = 0.9) were not significantly different between the two groups. The two groups did not differ at any time with respect to AUCs, nephrotoxicity, hepatotoxicity, or electrolyte disturbance.

Conclusion: The study suggested that the 2 h/12 h regimen is non-inferior to the conventional regimen (22 h CI/24 h) in terms of aGVHD incidence and adverse events. Further research is necessary to validate these findings and to guide practice, considering the small sample size of this study.

Trial registration: ClinicalTrials.gov identifier NCT04575779 with initial release on 19 September 2020-Retrospectively registered, https://clinicaltrials.gov/study/NCT04575779 .

Background: Elinzanetant is a dual neurokinin-1,3 receptor antagonist in development for the treatment of menopausal vasomotor symptoms. The objectives of these studies were to characterize the mass balance and biotransformation of elinzanetant.

Methods: In the clinical evaluation, whole blood, plasma, urine, and feces were collected from healthy fasted male volunteers (n = 6) following a single dose of 120 mg [¹⁴C]-elinzanetant oral suspension for analysis of total radioactivity and metabolite profiling. In vitro reaction phenotyping and kinetics experiments on enzymes involved in elinzanetant metabolism were performed.

Results: On average, 90.8% of the total radioactivity administered was recovered in excreta over 480 h, mostly via the fecal route (feces 90.4%; urine 0.4%). Elinzanetant was rapidly absorbed and extensively metabolized but remained the main circulating species in plasma, accounting for 39.1% of total radioactivity. Known principal and active metabolites M27, M30/34, and M18/21 accounted for 7.6%, 13.7%, and 4.9% of total radioactivity in plasma, respectively. All other radiolabeled plasma components were each < 3.5%, revealing the oxidation product M30/34 as the only metabolite with relevant exposure (> 10% of total radioactivity). In feces, metabolites resulting from oxidative biotransformation accounted, in sum, for ~ 40% of the dose, while elinzanetant remained the primary drug-related moiety. Results of in vitro experiments indicated that metabolism of elinzanetant was primarily mediated by cytochrome P450 3A4, with minor contribution from uridine 5'-diphospho-glucuronosyltransferase.

Conclusions: Elinzanetant is metabolized mainly via oxidative biotransformation mediated by cytochrome P450 3A4, and primarily excreted in feces. The primary oxidation product M30/34 is a major human metabolite of elinzanetant.

Trial registration number: NCT04654897.