A theoretical study of the optical absorption band shape for xenon hexafluoride

The classical Franck–Condon approximation is used together with the Monte Carlo integration technique to calculate the optical absorption band shape arising in xenon hexafluoride from the pseudo‐Jahn–Teller active t1u bending mode. The potential energy function for this mode has the Devonshire form for the hindered rotational motion of a diatomic molecule in a cubic site and is characterized by three parameters. Results are presented using values of these parameters as determined by Pitzer and Bernstein for the 1A1g electronic ground state and as estimated by us from the crystal‐field model of Wang and Lohr for the 1T1u and 3T1u electronic excited states.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71170/2/JCPSA6-67-5-1935-1.pd

Disposition and metabolism of [¹⁴C]-galunisertib, a TGF-<b>β</b>RI kinase/ALK5 inhibitor, following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics

<p>1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [¹⁴C]-galunisertib (100 µCi) to six healthy human subjects.</p> <p>2. The galunisertib plasma half-life was 8.6 h, while the ¹⁴C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the ¹⁴C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024 h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib.</p> <p>3. The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slow <i>in vitro</i> metabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile.</p> <p>4. Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib.</p

Utilizing ¹⁹F NMR to investigate drug disposition early in drug discovery

<div><p></p><p>1. Nuclear magnetic resonance (NMR), a non-selective and inherently quantitative method, has not been widely used as a quantitative tool for characterizing the disposition of lead molecules prior to clinical development. As a test case, we have chosen a fluoropyrimidine compound in lead optimization phase and evaluated its disposition following oral administration to rats using ¹⁹F NMR.</p><p>2. Urine, bile and feces from individual rats were profiled and the amount of dose eliminated in each matrix was calculated. The results indicated that, in male rats, the mean dose eliminated over 0–48 h was 40%, with 28% in urine, 9% in bile and 3% in feces. In female rats, the mean dose recovered in excreta over the same period was 55%, with 40% in urine, 8% in bile and 7% in feces.</p><p>3. In addition, plasma from rats and plasma from toxicology study in dogs were also profiled and exposure of circulating entities was determined. Plasma exposure determined by ¹⁹F NMR was in good agreement with those determined by conventional LC-MS/MS method, suggesting quantitative ¹⁹F NMR can be reliably used to estimate single dose or steady-state systemic exposure of circulating entities in animals and humans.</p></div