Physiologically based pharmacokinetic (PBPK) modeling and
simulation can be used to predict the pharmacokinetic behavior of drugs in humans
using preclinical data. It can also explore the effects of various physiologic
parameters such as age, ethnicity, or disease status on human pharmacokinetics, as
well as guide dose and dose regiment selection and aid drug–drug interaction risk
assessment. PBPK modeling has developed rapidly in the last decade within both the
field of academia and the pharmaceutical industry, and has become an integral tool in
drug discovery and development. In this mini-review, the concept and methodology of
PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK
modeling and simulation can be utilized through various stages of drug discovery and
development. These case studies are from our own work and the literature for better
understanding of the absorption, distribution, metabolism and excretion (ADME) of a
drug candidate, and the applications to increase efficiency, reduce the need for
animal studies, and perhaps to replace clinical trials. The regulatory acceptance and
industrial practices around PBPK modeling and simulation is also
discussed.
The dinuclear copper(II) cryptate [Cu2L](ClO4)4 (1) cleaves the C-C bond of acetonitrile at room temperature to produce a cyanide bridged complex of [Cu2L(CN)](ClO4)3.2CH3CN.4H2O (2). The cleavage mechanism is presented on the basis of the results of the crystal structure of 2, electronic absorption spectra, ESI-MS spectroscopy, and GC spectra of 1, respectively.
Radix Angelicae dahuricae is a well-known medicinal herb in a number of herb preparations for medical uses. In this study, a rapid and selective method using liquid chromatography with tandem mass spectrometry was developed for the separation and simultaneous quantitation of nine furanocoumarins from Radix A. dahuricae, namely imperatorin, isoimperatorin, oxypeucedanin hydrate, bergapten, oxypeucedanin, xanthotoxol, xanthotoxin, isopimpinellin, and psoralen. Chromatographic separation was achieved on a CAPCELL PAK MG II C18 analytical column. Detection was performed using positive electrospray ion source in the multiple reaction monitoring mode. The method was fully validated for analyzing these principles in rat plasma with a lower limit of quantification from 0.5 to 5 ng/mL. The intra- and interbatch precisions were less than 10%, and the accuracies ranged from -7.5 to 8.0%. The extraction recovery of the analytes was above 70% without a significant matrix effect. The method was used to determine the oral and intravenous pharmacokinetic profiles of these furanocoumarins after dosing with Radix A. dahurica extract. The bioavailability of these furanocoumarins ranged from 10.1 to 82.8%. These data provide critical information for a better understanding of the pharmacological mechanisms and herb-drug interaction potential of Radix A. dahurica.
Triptolide (TP) is the major active principle of Tripterygium wilfordii Hook f. and very effective in treatment of autoimmune diseases. However, TP induced hepatotoxicity limited its clinical applications. Our previous study found that TP was a substrate of P-glycoprotein and its hepatobiliary clearance was markedly affected by P-gp modulation in sandwich-cultured rat hepatocytes. In this study, small interfering RNA (siRNA) and specific inhibitor tariquidar were used to investigate the impact of P-gp down regulation on TP-induced hepatotoxicity. The results showed that when the function of P-gp was inhibited by mdr1a-1 siRNA or tariquidar, the systemic and hepatic exposures of TP were significantly increased. The aggravated hepatotoxicity was evidenced with the remarkably lifted levels of serum biomarkers (ALT and AST) and pathological changes in liver. The other toxicological indicators (MDA, SOD and Bcl-2/Bax) were also significantly changed by P-gp inhibition. The data analysis showed that the increase of TP exposure in mice was quantitatively correlated to the enhanced hepatotoxicity, and the hepatic exposure was more relevant to the toxicity. P-gp mediated clearance played a significant role in TP detoxification. The risk of herb-drug interaction likely occurs when TP is concomitant with P-gp inhibitors or substrates in clinic.
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug-drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.
The crystal structures of [Co 2L(Cl)](ClO 4) 3 ( 1), [Co 2L(Br)](ClO 4) 3 ( 2), [Co 2L(OH)(OH 2)]I 3 ( 3), and [Co 2L (1)(Cl)](ClO 4) 3 ( 4), the density functional theory calculations, as well as the binding constants of [Co 2L] (4+) toward Cl (-) and Br (-) and of [Co 2L (1)] (4+) toward Cl (-), are reported in this paper (L = N[(CH 2) 2NHCH 2(C 6H 4- p)CH 2NH(CH 2) 2] 3N, L (1) = N[(CH 2) 2NHCH 2(C 6H 4- m)CH 2NH(CH 2) 2] 3N). The rigid dicobalt(II) cryptate [Co 2L] (4+) shows the recognition of Cl (-) and Br (-) but not of F (-) and I (-), because of the size matching to its rigid cavity. We also found that the relative rigid tripodal skeleton of L than that of L (1) results in the higher affinity of [Co 2L] (4+) toward Cl (-). Magnetic susceptibility measurements of 1 and 2 indicate that the two Co(II) atoms in the cryptates are antiferromagnetically coupled through the Cl (-)/Br (-) bridge, with g = 2.19, J = -13.7 cm (-1) for 1, and g = 2.22, J = -17.1 cm (-1) for 2.
Triptolide (TP), a main bioactive component of Tripterygium wilfordii Hook F., is a promising agent for treatment of autoimmune diseases. However, a high incidence of dose-limiting hepatotoxicity was observed in the clinic. Sandwich-cultured rat hepatocyte model was used in this study to identify the involvement of P-glycoprotein (P-gp) in TP disposition and to evaluate TP-induced hepatotoxicity after modulation of P-gp by the known inhibitors, ritonavir and tariquidar, and known inducers, phenobarbital, quercetin, and H 2 O 2 . Our data showed that biliary clearance of TP reduced 73.7% and 84.2% upon treatment of ritonavir (25 mM) and tariquidar (5 mM), respectively. In contrast, increases of 346%, 280%, and 273% in biliary clearance of TP were observed with treatment of phenobarbital (1.0 mM), quercetin (20 mM), and H 2 O 2 (0.5 mM), respectively. The TP-induced hepatotoxicity increased by twofold when CYP activity was blocked by 1-aminobenzotriazole, suggesting that CYP and P-gp may both contribute to the detoxification of TP in the SCRH model. In addition, hepatotoxicity and the expression of apoptosis proteins Bax and Bcl-2 were correlated qualitatively with the TP exposure duration and its intracellular concentration, which, in turn, can be modulated by P-gp inhibitors or inducers. Our results for the first time demonstrated that in addition to CYP-mediated metabolism, P-gp also plays an important role in the disposition of TP and TP-induced hepatotoxicity. Thus, the modulation of canalicular P-gp has a potential to cause drug-drug interaction between TP and the coadministered P-gp inhibitors or inducers in the clinic.
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