\n\nAn in
silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly HSP990 Cytoskeletal Signaling inhibitor basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (Cl) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media. Drug precipitation in the small intestine was estimated from crystal growth theory. GI parameters (gastric emptying rate and fluid volume) appropriate to the dosing conditions (fasting and fed states) were used in the PBPK model. The disposition parameters of nelfinavir were estimated by fitting compartmental models to the in vivo oral PK data. The in vivo performance in each prandial state was simulated with the PBPK model, and predicted values for AUC and C(max) were compared to observed values.\n\nDissolution results in FaSSIF-V2 and FeSSIF-V2, simulating the fasting and fed small intestinal conditions, respectively, correctly predicted that there would be a positive food effect for nelfinavir AZD4547 molecular weight mesylate, but overestimated the food effect observed in healthy human volunteers. In order to better predict the food effect, an in silico PBPK simulation model using STELLA software was evolved.
Results with the model indicated that invoking drug precipitation in the small intestine is necessary to describe the in vivo performance of nelfinavir mesylate in the fasted state, whereas a good prediction under fed state conditions is obtained without assuming any precipitation. In vitro-in silico-in vivo relationships (IVISIV-R) may thus be a helpful tool in understanding the critical parameters that affect the oral absorption of poorly soluble weak bases. (C) 2011 Elsevier B.V. All rights reserved.”
“Sterile alpha motif domain-containing 11
(SAMD11) is evolutionarily conserved from zebrafish to human. Mouse Samd11 is predominantly expressed in developing retinal photoreceptors and the adult pineal gland, and its transcription is directly regulated by Z-DEVD-FMK the cone-rod homeodomain protein Crx. However, there has been little research on human SAMD11. To investigate the function of human SAMD11, we first cloned its coding sequence (CDS) and identified up to 45 novel alternative splice variants (ASVs). Mouse Samd11 ASVs were also identified by aligning the mouse Samd11 expressed sequence tags (ESTs) with the annotated sequence. However, the range of expression and transcriptional regulation of SAMD11 differs between human and mouse. Human SAMD11 was found to be widely expressed in many cell lines and ocular tissues and its transcription was not regulated by CRX, OTX2 or NR2E3 proteins.