Biopharmaceutics & Drug Disposition最新文献

Tacrolimus is widely used in organ transplantation to prevent rejection. However, the narrow therapeutic window and the large inter-and intra-individual variability in the pharmacokinetics (PK) of tacrolimus make it difficult for individualization of dosing. This study aimed at developing a population pharmacokinetic model for estimating the oral clearance of tacrolimus in Chinese liver transplant patients, and identifying factors that contribute to the PK variability of tacrolimus. Data of 151 liver transplant patients who received tacrolimus were analyzed in this study. The population PK model was analyzed and the covariates including population demographic and biochemical characteristics, drug combination, and genetic polymorphism were explored using non-linear mixed-effects modeling approach. A single-compartment population PK model was developed, and the final model was CL/F = (14.6–2.38 × cytochrome P450 (CYP) 3A5−3.72 × WZC+1.04 × (POD/9)+2.48 × COR) × Exp(η_i), where CYP3A5 was 1 for CYP3A5*3/*3, Wuzhi Capsule (WZC) was 1 when patients took tacrolimus combined with WZC, otherwise it was 0, corticosteroids (COR) was 1 when patients take tacrolimus combined with COR, otherwise, it was 0, POD was the post-operative day. Visual inspection and bootstrap indicated that the final model was stable and robust. In this study, we developed the first tacrolimus population PK model in Chinese adult liver transplant patients. We first determined the influence of WZC on tacrolimus in these people, which could provide useful PK information for the drug combination of tacrolimus and WZC. We also revealed the influence of genetic polymorphism of CYP3A5, POD, and a combination of COR on tacrolimus PK. Therefore, these significant factors should be taken into consideration in optimizing dosage regimens.

The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-life of KRM-II-81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5-KRM-II-81) that could be evaluated as a potentially longer-acting analog. In contrast to computer predictions, peak plasma concentrations of D5-KRM-II-81 in rats were not significantly greater than those produced by KRM-II-81 after oral administration. Furthermore, brain disposition of KRM-II-81 was higher than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the t_max for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. Non-metabolic considerations might be relevant to the lack of increases in exposure by D5-KRM-II-81. Alternative sites of metabolism on KRM-II-81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5-KRM-II-81.

Wuzhi capsule (WZC), a preparation of Fructus Schisandra sphenanthera extract, has been used widely for the treatment of viral and drug-induced hepatitis in China. This study aimed to determine the pharmacokinetic parameters of tacrolimus (TAC) when co-administered with WZC and the dose-effect of WZC on tacrolimus in healthy volunteers. The effect of an increased dosage of WZC (1, 2, 6, and 8 capsules once daily) on the relative oral exposure of tacrolimus was assessed to explore the dose–response relationship between WZC and tacrolimus using bioanalysis, pharmacokinetic, and genotypical analyses. The influence of CYP3A5 and MDR1 genetic polymorphisms on the WZC dose was elucidated by maintaining the C_trough of tacrolimus in Chinese healthy volunteers. When co-administered with WZC, the T_max of tacrolimus was increased significantly while the apparent oral clearance was decreased. The plasma tacrolimus level in volunteers with high CYP3A5 expression was much lower than that in those with mutant CYP3A5. However, polymorphisms of MDR1 exon26 C3435T, exon21 G2677T/A, and exon12 C1236T were not associated with plasma tacrolimus levels. Our findings provide important information on interactions between modern medications and herbal products, thus facilitating a better usage of tacrolimus in patients receiving WZC.

Febuxostat is a second-line xanthine oxidase inhibitor that undergoes extensive hepatic metabolism to yield its major acyl-β-D-glucuronide metabolite (febuxostat AG). It was recently reported that febuxostat inhibited organic anion transporter 3 (OAT3)-mediated uptake of enalaprilat. Here, we investigated the inhibition of febuxostat and febuxostat AG on OAT3 in transfected human embryonic kidney 293 cells. Our transporter inhibition assays confirmed the potent noncompetitive and competitive inhibition of OAT3-mediated estrone-3-sulfate transport by febuxostat and febuxostat AG with corresponding apparent K_i values of 0.55 and 6.11 μM respectively. After accounting for probe substrate-dependency and protein binding effects, mechanistic static modelling with the direct factor Xa anticoagulant rivaroxaban estimated a 1.47-fold increase in its systemic exposure when co-administered with febuxostat based on OAT3 interaction which in turn exacerbates the bleeding risk from baseline for patients with atrial fibrillation by 1.51-fold. Taken together, our results suggested that the concomitant usage of febuxostat with rivaroxaban may potentially culminate in a clinically-significant drug-drug interaction and result in an increased risk of bleeding as a result of its OAT3 inhibition.

Carbonic anhydrases (CAs, Enzyme Commission 4.2.1.1) convert carbon dioxide to bicarbonate in metabolism and use Zn²⁺ ions as a cofactor for their catalytic activity. The activators or inhibitors of CA-I and CA-II, which are the most abundant CA isozymes in erythrocytes, have pharmacological applications in medicine. So, investigation of drug-protein interaction of these isozymes is significant. On this basis, the objective of this study was to clarify the primer effects of widely used drugs on the activity of human CA-I and CA-II enzymes and elucidate the inhibition mechanism through molecular docking studies. For this aim isozymes were purified from human erythrocytes by affinity chromatography technique. Then inhibition profiles of antiulcer, glucocorticoids, and urological drugs were investigated. As a result, while budesonide had the highest inhibitory potency on hydratase activity of hCA-I with the IC₅₀ of 0.08 mM, levofloxacin showed the highest inhibition effect on hCA-II with the IC₅₀ of 0.886 mM. The most effective inhibitor on the esterase activity of isozymes was found as fluticasone propionate with the K_i values of 0.0365 ± 0.016 mM and 0.054 ± 0.018 mM respectively. However, by molecular docking study, it was estimated that budesonide showed maximum inhibition potency for both isozymes with the free binding energy of −7.58 and −6.97 kcal/mol, respectively. Consequently, it was observed that some of the drugs studied did not show any inhibitory effect. Drug-enzyme interactions were also estimated by molecular docking. This study could contribute to the discovery of new drug candidates and as well as target proteins.

The study assessed the site dependent intestinal absorption of Daclatasvir and investigated the effects of piperine and omeprazole on such absorption utilizing in situ rabbit intestinal perfusion technique. The intestinal absorption of Daclatasvir was assessed in four segments: duodenum, jejunum, ileum, and colon. The effect of co-perfusion with omeprazole was monitored through the tested anatomical sites. The effect of piperine, a P-glycoprotein (P-gp) inhibitor on Daclatasvir absorption from jejunum and ileum was tested. The results showed that Daclatasvir was incompletely absorbed from the rabbit small and large intestine. The absorptive clearance per unit length (PeA/L) was site dependent and was ranked as colon > duodenum > jejunum > ileum. This rank is the opposite of the rank of P-gp intestinal content suggesting possible influence for P-gp. Co-perfusion with omeprazole increased PeA/L and this was evidenced also with reduced the L95% of Daclatasvir from both small and large intestinal segments. Significant enhancement in Daclatasvir absorption through jejunum and ileum was shown in presence of piperine. Daclatasvir showed site dependent intestinal absorption in a manner suggesting its affection by P-gp efflux. This effect was inhibited by piperine. Co-administration of Daclatasvir with omeprazole can enhance intestinal absorption a phenomenon which requires extension to human pharmacokinetic investigation.

Sumatriptan was introduced in 1983, as the first of the triptans, selective 5-hydroxytryptamine (5-HT_1B/1D) receptor agonists, to treat moderate to severe migraine. Migraine predominates in females. Although there have been reports of sex differences in migraine-associated features and pharmacokinetics (PKs) of some triptans, sex differences in the PKs of oral sumatriptan have never been evaluated in Korean. We conducted this study of oral sumatriptan to assess the sex differences in Korean population. Thirty-eight healthy Korean subjects who participated in two separate clinical studies receiving a single oral dose of 50 mg sumatriptan with the same protocols were included in this analysis. A total of 532 sumatriptan concentration observations were used for a population PK modeling. Validation of final population PK model of sumatriptan was performed using bootstrap and visual predictive check. The PK profile of oral sumatriptan was adequately described by a one-compartmental model with combined transit compartment model and a first-order absorption. The covariate analysis showed that the clearance of oral sumatriptan was significantly higher in males than in females (male: 444 L/h, female: 281 L/h). Our results showed that there were sex differences in the clearance of oral sumatriptan. These results encourage further studies to establish the sumatriptan pharmacokinetic–pharmacodynamic model considering sex-related PK differences, which may help to determine optimal dosing regimens for effective treatment of migraine in males and females. Clinical trial registration: CRIS Registration No. KCT0001784.

Xanthohumol, a natural isoflavone from Humulus lupulus L., possesses biological activities. However, the biological fate of xanthohumol in vivo remains unclear. The aim of this study was to investigate the absorption and metabolism of xanthohumol in rats through UPLC-MS/MS. The plasma, urine and fecal samples were collected after oral administration of xanthohumol (25, 50, 100 mg/kg) in SD rats. The contents of xanthohumol and its metabolites were determined by UPLC-MS/MS. A total of 6 metabolites of xanthohumol were identified in rats, including methylated, glucuronidated, acid-catalyzed cyclization and oxidation, indicating xanthohumol underwent phase I and II metabolism. Besides, isoxanthohumol was the major metabolites of xanthohumol. Xanthohumol was rapidly absorbed, metabolized, and eliminated in rats. The pharmacokinetics results showed the T_max of xanthohumol and isoxanthohumol were 3 and 2.33 h, respectively. The AUC_0−t of xanthohumol and isoxanthohumol were 138.83 ± 6.03 and 38.77 ± 4.46 ng/ml·h, respectively. Furthermore, xanthohumol was mainly excreted in the form of prototype through feces and a small amount of xanthohumol was excreted through urine. These results illustrated the absorption, metabolism, and pharmacokinetics process of xanthohumol in rats, and provided a reference for the further rational applications.