Pharmacokinetic Mathematical Model Research Articles

Dynamic chromatopharmacokinetics model for components in Chinese medicine and validation in Buyang Huanwu Decoction

The Chinese medicine is mostly derived from plants or animals, highly polymorphic, with dynamic components which are reflected by the characteristic peaks and fingerprint peaks in chromatographic fingerprints. The chromatopharmacokinetics method for determined components is not applicable due to dynamic changes of chromatopharmacokinetics. Based on the preliminary study, dynamic pharmacokinetics mathematical model for multiple components in Chinese medicine was set up and verified by Buyang Huanwu Decoction as the model drug, applying the principle of the total quantum statistical moment(TQSM), superimposing or subtracting the relevant statistical parameters in blood samples and blank samples. This provided a new method for the chromatopharmacokinetic study of Chinese medicine. HPLC was used to determine the TQSM parameters in blood and blank sample fingerprints of Buyang Huanwu Decoction at each point, and the overall TQSM parameters of drug-containing blood sample and blank samples were obtained with addition calculation of TQSM; while the initial TQSM of the pure drug can be obtained with subtraction calculation. The metabolic and absorption equilibrium constants were calculated iteratively to a steady state using the estimated metabolic equilibrium constants, then the metabolic chromatopharmacokinetic parameters in rats were obtained: VUC_T 1.262×10~8 mAu·s, MRT_T 37.48 h, VRT_T 9.016×10~2 h~2, CL_T 25.79 mL·h~(-1)·kg~(-1), Vs 1.586×10~2 mL·kg~(-1), t_(T,0.5) 6.15 h, respectively. This suggested that 95% of the compounds in whole recipe were metabolized and secreted from the body after 0-96.33 h. The experiment verified that the established mathematical model and the total quantum moment statistics parameters can represent the dose-time relationship of Buyang Huanwu Decoction, which can be used to study on in vivo metabolism dynamics for Chinese medicine.

Ultrasensitive tumour-penetrating nanosensors of protease activity.

The ability to identify cancer lesions with endogenous biomarkers is currently limited to tumours ~1 cm in diameter. We recently reported an exogenously administered tumour-penetrating nanosensor that sheds, in response to tumour-specific proteases, peptide fragments that can then be detected in the urine. Here, we report the optimization, informed by a pharmacokinetic mathematical model, of the surface presentation of the peptide substrates to both enhance on-target protease cleavage and minimize off-target cleavage, and of the functionalization of the nanosensors with tumour-penetrating ligands that engage active trafficking pathways to increase activation in the tumour microenvironment. The resulting nanosensor discriminated sub-5 mm lesions in human epithelial tumours and detected nodules with median diameters smaller than 2 mm in an orthotopic model of ovarian cancer. We also demonstrate enhanced receptor-dependent specificity of signal generation in the urine in an immunocompetent model of colorectal liver metastases, and in situ activation of the nanosensors in human tumour microarrays when re-engineered as fluorogenic zymography probes.

BODIPY-Conjugated Xyloside Primes Fluorescent Glycosaminoglycans in the Inner Ear of Opsanus tau

We report on a new xyloside conjugated to BODIPY, BX and its utility to prime fluorescent glycosaminoglycans (BX-GAGs) within the inner ear in vivo. When BX is administered directly into the endolymphatic space of the oyster toadfish (Opsanus tau) inner ear, fluorescent BX-GAGs are primed and become visible in the sensory epithelia of the semicircular canals, utricle, and saccule. Confocal and 2-photon microscopy of vestibular organs fixed 4h following BX treatment, reveal BX-GAGs constituting glycocalyces that envelop hair cell kinocilium, nerve fibers, and capillaries. In the presence of GAG-specific enzymes, the BX-GAG signals are diminished, suggesting that chondroitin sulfates are the primary GAGs primed by BX. Results are consistent with similar click-xylosides in CHO cell lines, where the xyloside enters the Golgi and preferentially initiates chondroitin sulfate B production. Introduction of BX produces a temporary block of hair cell mechanoelectrical transduction (MET) currents in the crista, reduction in background discharge rate of afferent neurons, and a reduction in sensitivity to physiological stimulation. A six-degree-of-freedom pharmacokinetic mathematical model has been applied to interpret the time course and spatial distribution of BX and BX-GAGs. Results demonstrate a new optical approach to study GAG biology in the inner ear, for tracking synthesis and localization in real time.

Applications of supercritical fluids to enhance the dissolution behaviors of Furosemide by generation of microparticles and solid dispersions

The ‘classical’ loop diuretic drug Furosemide has been used as a model compound to investigate the possibility of enhancing the dissolution rate of poorly water-soluble drugs using supercritical anti-solvent techniques (SASs).In the present study we report upon the in vitro bioavailability improvement of Furosemide through particle size reduction as well as formation of solid dispersions (SDs) using the hydrophilic polymer Crospovidone. Supercritical carbon dioxide was used as the processing medium for these experiments.In order to successfully design a CO2 antisolvent process, preliminary studies of Furosemide microparticles generation were conducted using Peng Robinson’s Equation of State. These preliminary studies indicated using acetone as a solvent with pressures of 100 and 200bar and a temperature of 313K would yield optimum results. These operative conditions were then adopted for the SDs. Micronization by means of SAS at 200bar resulted in a significant reduction of crystallites, particle size, as well as improved dissolution rate in comparison with untreated drug. Furosemide recrystallized by SAS at 100bar and using traditional solvent evaporation. Moreover, changes in polymorphic form were observed in the 200bar samples.The physicochemical characterization of Furosemide:crospovidone SDs (1:1 and 1:2 w/w, respectively) generated by SAS revealed the presence of the drug amorphously dispersed in the 1:2 w/w sample at 100bar still remaining stable after 6months. This sample exhibits the best in vitro dissolution performance in the simulated gastric fluid (pH 1.2), in comparison with the same SD obtained by traditional method. No interactions between drug and polymer were observed.These results, together with the presence of the selected carrier, confirm that the use of Supercritical fluids antisolvent technology is a valid mean to increase the dissolution rate of poorly soluble drugs.Theoretical in vivo–in vitro relation was predicted by means of a pharmacokinetics mathematical model.

Doxorubicin-Loaded Zein <i>in Situ</i> Gel for Interstitial Chemotherapy

A novel drug delivery system of doxorubicin (DOX)-loaded Zein in situ gel for interstitial chemotherapy was investigated in this study. The possible mechanisms of drug release were described according to morphological analysis by optical microscopy and scanning electronic microscope (SEM). In vitro and in vivo anti-tumor activity studies showed that DOX-loaded Zein in situ gel was superior to DOX solution. Local pharmacokinetics in tumor tissue was studied by quantitative analysis with confocal laser scanning microscopy (CLSM) combined with microdialysis technology. A pharmacokinetics mathematical model of DOX-loaded Zein in situ gel in tumors was then built.

A theoretical approach for activation of a pro-drug by its conjugate and its localization in cancer chemotherapy

We develop a two-step pharmacokinetic mathematical model for drug distribution in the case of a human body having a solid tumor. The concentration of a conjugate in micro-vessels and in tissue is considered in the form of different compartments. The model aims at studying bio-distribution, pharmacokinetics and conjugate permeability in the case of cancer chemotherapy. In earlier studies on this topic the chemical reactions (constructive or destructive) have not been considered. We include chemical reactions in the tissue concentration. The concentrations in micro vessels and the tumor are obtained using compartment analysis. The dosing of the conjugate may be by heavy injection, multiple injections or infusion.

A technical note concerning non-adherence to drug therapy: exact expressions for the mean and variance of drug concentration

There is considerable evidence that prescribed drugs are not taken as intended. We present a stochastic pharmacokinetic mathematical model that can be used to assess the implications of non-adherence to prescribed drug regimens, on the part of either patients or health professionals. In the context of an orally administered drug, explicit equations are derived for the time varying mean and variance of the concentration of the drug in the serum, depending on the probability of each scheduled administration being omitted. The analysis presented here can be used to assess whether a given level of non-adherence is likely to have a clinical impact. The methods used can easily be adapted for use in the context of other routes of drug administration.

Simultaneous modelling of a nonlinear multiresponse pharmacokinetic system

Concentration-time curves of an anticancer drug and two of its metabolites were analyzed simultaneously by using a pharmacokinetic mathematical model. The nonlinearities observed in the collected data of the first metabolite could be explained by enzymatic pathways; therefore the model proposed in this paper is an enzymatic nonlinear model. The simultaneous modelling of the three concentration- time curves introduces, at a given time, the concept of a multivariate measurement error, with a zero mean multinormal distribution and a fixed structure of the variance model. The maximum likelihood principle used as an estimation criterion allows the separation of pharmacokinetic model and error variance model parameters. For model validation we a posteriori verify by residual analysis the hypotheses postulated on the error at the beginning. This methodology introduces intrakinetic and interkinetic variabilities, which provide an automatic weighting between successive measurements and between entire concentration-time curves, respectively.