Intermolecular correlations of liquid and glassy CS2 studied by synchrotron radiation x-ray diffraction.

How is the orientation of molecular liquids ordered on cooling? What are the basic structures of molecular glasses, e.g., close to the crystalline structure or some special structures such as icosahedral cluster? These are long-standing questions in liquid and glass physics. We have constructed a novel cryostat to prepare simple molecular glasses by vapor deposition and performed in situ synchrotron radiation x-ray diffraction experiments. The glassy state of a simple molecule CS2, which cannot be vitrified by normal liquid quenching, was successfully prepared with this instrument, and its diffraction data were collected in a wide Q-range of 0.16-25.7 Å-1 with a high-energy diffractometer at BL04B2, SPring-8. The diffraction data of liquid CS2 were also recorded in a wide temperature range of 160-300 K. These diffraction data were analyzed with molecular dynamics simulations and reverse Monte Carlo modelings to investigate orientational correlation. From the obtained 3D structure models, the orientational correlation between neighboring CS2 molecules was investigated quantitatively as a function of temperature. At room temperature, the parallel and T-shaped arrangements are preferred for the nearest neighbor correlation. On cooling, these arrangements are developed gradually, and its rate became prominent below the melting temperature (162 K). In the glassy state, the slipped-parallel arrangement is dominant as well as the T-shaped arrangement. Both arrangements appear in the CS2 crystal, indicating that the structure of glassy CS2 is close to that of crystalline CS2.

A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data.

BACKGROUND AND OBJECTIVE: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug's therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. METHODS: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. RESULTS: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug-metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. CONCLUSION: The developed PBPK model can be regarded as the first step towards a PBPK-pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.

A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans.

BACKGROUND AND PURPOSE: Alvespimycin, a new generation of heat shock protein 90 (Hsp90) inhibitor in clinical trial, is a promising therapeutic agent for cancer. Pharmacokinetic models of alvespimycin would help in the understanding of drug disposition, predicting drug exposure and interpreting dose-response relationship. In the present study we aimed to develop a physiologically based pharmacokinetic (PBPK) model of alvespimycin in mice and evaluate the utility of the model for predicting alvespimycin disposition in other species. EXPERIMENTAL APPROACH: A literature search was performed to collect pharmacokinetic data for alvespimycin. A PBPK model was initially constructed to demonstrate the disposition of alvespimycin in mice, and then extrapolated to rats and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters. KEY RESULTS: A PBPK model, employing a permeability-limited model structure and saturable tissue binding, was built in mice. It successfully characterized the time course of the disposition of alvespimycin in mice. After extrapolation to rats, the model simulated the alvespimycin concentration-time profiles in rat tissues with acceptable accuracies. Likewise, a reasonable match was found between the observed and simulated human plasma pharmacokinetics of alvespimycin. CONCLUSIONS AND IMPLICATIONS: The PBPK model described here is beneficial to the understanding and prediction of the effects of alvespimycin in different species. It also provides a good basis for further development, which necessitates additional studies, especially those needed to clarify the in-depth mechanism of alvespimycin elimination. A refined PBPK model would benefit the understanding of dose-response relationships and optimization of dosing regimens.

Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis.

Life-threatening diarrhoea is observed in up to 25% of cancer patients receiving irinotecan. The associations between the UGT1A1*28 polymorphism and irinotecan-induced diarrhoea remains controversial because of conflicting data in the literature. Meta-analyses were performed on published data in terms of relationships between UGT1A1*28 and severe diarrhoea. We searched databases for relevant studies that were published in English or Chinese. Two reviewers extracted data and assessed methodological quality. UGT1A1*28 related odds ratios (ORs) were pooled by use of a fixed-effects model. The studies included were stratified into subgroups representing different races and irinotecan doses, and meta-regression analyses were performed to investigate the effect of study characteristics on the association between UGT1A1*28 and diarrhoea. Twenty trials including a total of 1760 cancer patients were included. The risk of severe diarrhoea at medium and high irinotecan doses was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 genotype (OR=3.69, 95% confidence interval [CI]=2.00-6.83; P<0.001). Considering the patients with a UGT1A1*1/*28 genotype, the risk of toxicity was also higher than among those with a wild-type genotype at medium and high doses (OR=1.92, 95% CI=1.31-2.82; P=0.001). No association was observed between UGT1A1*28 and severe diarrhoea at low doses (<125 mg/m(2)). In conclusion, patients carrying UGT1A1*28 allele(s) are at an increased risk of irinotecan-induced severe diarrhoea. This increased risk is only apparent in those who are administrated with medium or high irinotecan doses.