Drug Distribution In Organs Research Articles

Determination of drug distributions in decomposed and buried postmortem tissues and bones of pigs administered of drugs

Interpretation of drug levels in decomposed and buried corpses is difficult. We aimed to determine postmortem distribution of drugs in putrefied-decomposed visceral tissues and buried bones, and the effect of decomposition and burial on distribution of drugs in organs and bone tissues by administering drug groups selected from various drug classes to domestic pigs. Pigs were divided into groups (n = 5) and dosed with a variety of drugs. Peripheral blood, organ and bone samples in different anatomical locations were collected from pigs killed. Organ samples were collected at postmortem 4th, 24th, 48th, 72nd and 96th hour. Then the corpses were buried below soil ground. Bone samples from buried corpses were collected at 5th and 10th months of the burial time by exhumation. All samples were analysed using liquid chromatography-tandem mass spectrometry after making sample preparation using appropriate methods. Only 10 of the 14 drugs were detected in the initial peripheral blood. For all bone types analyzed, highest drug levels were detected at thorax region and lowest drug levels were detected at the lower extremity. Given the fact that most of the soft tissue is located in the thorax region, it is possible that during the decomposition process, drugs partitioned from the liquefied tissue into bones. That the drug levels in bones decreased was observed when exhumation was done at 10th month of the burial time. Drug distribution in organ and bone of decomposed and burial corpses vary due to unknown mechanisms and completely unexplained conditions such as postmortem redistribution.

Development of High-resolution Methods for the Analysis of Drug Distribution in Biological Tissue Samples and Their Applications

The abuse of drugs has become a serious social problem worldwide. Amphetamine-type stimulants such as methamphetamine are recreationally abused and can cause toxic effects in the body. Unfortunately, death from drug poisoning can occur due to careless intake. In postmortem examinations, the distribution of drugs in an entire organ gives valuable information for evaluating their toxicity. We developed methods to measure the distribution of drugs in organs using LC/MS and matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). The complementary use of the two methods provides more detailed information on the distribution and concentration of drugs in organs because the accurate quantification in LC/MS and small spatial resolution in MALDI-IMS are combined. On the other hand, it is important to elucidate the drug intake history of suspects and victims in drug-facilitated crimes (DFCs). Hair and nail samples are often used to confirm chronic drug intake because ingested drugs can stably remain in these specimens over several months. However, it is impossible to determine the day of drug ingestion in conventional segmental analysis of bulk samples. Therefore, we developed methods to cut hair strands at 0.4-mm intervals and nails at 0.2-mm intervals, which correspond to their respective growth rates over 1-2 d, to analyze the drugs in each segment efficiently using LC/MS. The microsegmental hair analysis method is applied to estimate the day of drug ingestion in DFC investigations. These methods could be applied to measure the distribution of compounds in various solid samples.

Quantitative MALDI Imaging of Spatial Distributions and Dynamic Changes of Tetrandrine in Multiple Organs of Rats.

Detailed spatio-temporal information on drug distribution in organs is of paramount importance to assess drug clinically-relevant properties and potential side-effects. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as a label-free and sensitive imaging modality provides an additional means of accurately visualizing drug and its metabolites distributions in tissue sections. However, technical limitations, complex physiochemical environment of surface and low abundance of target drugs make quantitative MALDI imaging of drug and its metabolites quite challenging.Methods: In this study, an internal standard correction strategy was applied for quantitative MALDI imaging of tetrandrine in multiple organs of rats including lung, liver, kidney, spleen, and heart. The feasibility and reliability of the developed quantitative MSI method were validated by conventional liquid chromatography-tandem MS (LC-MS/MS) analysis, and the two methods showed a significant correlation.Results: The quantitative MALDI imaging method met the requirements of specificity, sensitivity and linearity. Tissue-specific spatio-temporal distribution patterns of tetrandrine in different organs were revealed after intravenous administration in the rat. Moreover, demethylated metabolite was detected in liver tissues.Conclusions: The current work illustrates that quantitative MALDI imaging provides an alternative means of accurately addressing the problem of drug and its metabolites distribution in tissues, complementary to traditional LC-MS/MS of tissue homogenates and whole-body autoradiography (WBA). Quantitative spatio-chemical information obtained here can improve our understanding of pharmacokinetics (PK), pharmacodynamics (PD), and potential transient toxicities of tetrandrine in organs, and possibly direct further optimization of drug properties to reduce drug-induced organ toxicity.

Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging.

The penetration of anticancer drugs in solid tumors is important to ensure the therapeutic effect, so methods are needed to understand drug distribution in different parts of the tumor. Mass spectrometry imaging (MSI) has great potential in this field to visualize drug distribution in organs and tumor tissues with good spatial resolution and superior specificity. We present an accurate and reproducible imaging method to investigate the variation of drug distribution in different parts of solid tumors. The method was applied to study the distribution of paclitaxel in three ovarian cancer models with different histopathological characteristics and in colon cancer (HCT116), breast cancer (MDA-MB-231) and malignant pleural mesothelioma (MPM487). The heterogeneous drug penetration in the tumors is evident from the MALDI imaging results and from the images analysis. The differences between the various models do not always relate to significant changes in drug content in tumor homogenate examined by classical HPLC analysis. The specificity of the method clarifies the heterogeneity of the drug distribution that is analyzed from a quantitative point of view too, highlighting how marked are the variations of paclitaxel amounts in different part of solid tumors.

Distribution measurement of amphetamine‐type stimulants in organs using micropulverized extraction and liquid chromatography/tandem mass spectrometry to complement drug distribution using mass spectrometry imaging

Amphetamine-type stimulants (ATS) such as methamphetamine are widely abused and can cause toxic effects in the body. In this study, a simple and accurate analytical method for distribution measurement of drugs in organs was developed to visualize localization of ATS in organs and to complement drug distribution by mass spectrometry imaging (MSI). The brain, liver and kidney from rats to which ATS had been administered were segmented into blocks of 2×2×2 mm3 at -30°C. Each organ block was micropulverized with a stainless-steel bullet at -80°C. The concentrations of drugs in each block were measured by liquid chromatography/tandem mass spectrometry. The three-dimensional distribution of drugs in a whole organ was expressed using color gradation of drug concentration after reconstruction of all blocks to the original locations. The distribution was also compared with that obtained by MSI. This method enabled measurement of drug distribution in organs with simple and clean procedures and accurate quantification unlike autoradiography and MSI. The methamphetamine concentrations were different between parts in an organ, particularly in the kidney. This method could be applicable to the measurement of the distribution of compounds in various solid samples and could be used as a complementary method for the measurement of the distribution of compounds by MSI.

Nanoparticle Missiles from Exploding Polyelectrolyte Capsules

Out with a bang! Microcapsules have been prepared which, as a result of an explosion triggered by an external stimulus, distribute nanoparticles throughout the local environment both efficiently and rapidly (see picture). In this way a principle found in nature for the dispersal of seeds and defensive materials has now been realized in nanotechnology and might be utilized, for example, for the better distribution of drugs in organs.

Determinants of drug delivery and transport to solid tumors

This presentation addresses the barriers and determinants and the importance of drug-induced apoptosis in drug transport and delivery to organs and solid tumors. In particular, we examined the roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution. Drug transport in bladder tissues is described by the distributed model which combined monodimensional Fickian diffusion and first order removal of drug by the perfusing blood. Microscopic evaluation of the spatial drug distribution in bladder, prostate and tongue indicates heterogeneous drug distribution with large and erratic concentration gradient. In general, drug distribution favors interstitial space and vasculature, with little penetration in muscles. Drug penetration into 3-dimensional solid tumors is typically 5- to 10-fold slower than in monolayer cultures. The transport of highly protein-bound drugs such as paclitaxel and doxorubicin in a solid tumor is retarded by a high tumor cell density and enhanced by drug-induced apoptosis. Accordingly, the delivery of a highly protein-bound drug to cells in a solid tumor is affected by its apoptotic effects and is therefore determined by the drug concentration and the treatment duration, i.e. treatment schedule. Under in vitro and in vivo conditions, the delivery of highly protein-bound drugs to tumor can be enhanced by using a pretreatment that induces apoptosis and reduction in cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition. In conclusion, in addition to the usual processes involved in drug transport such as distribution through vascular space, transport across microvessel walls, and diffusion through interstitial space in tumor tissue, other factors including tissue structure and composition and alteration by drug-induced apoptosis are important determinants of drug distribution in organs and solid tumors.

Efficacy of liposomal forms of cytostatics

Study of the toxicity and pharmacokinetics of free and liposomal forms of cytostatics revealed an appreciable decrease of the toxicity of high drug doses and prolongation of drug action in liposomes. The distribution of drugs in organs and tissues is shown.