A Simple Decision Tree Suited for Identification of Early Oral Drug Candidates With Likely Pharmacokinetic Nonlinearity by Intestinal CYP3A Saturation.

To identify oral drugs that likely display nonlinear pharmacokinetics due to saturable metabolism by intestinal CYP3A, our previous report using CYP3A substrate drugs proposed an approach using thresholds for the linear index number (LIN3A = dose/K; K, Michaelis-Menten constant for CYP3A) and the intestinal availability (FF). Here, we aimed to extend the validity of the previous approach using both CYP3A substrate and non-substrate drugs and to devise a decision tree suited for early drug candidates using in vitro metabolic intrinsic clearance (CL) instead of FF. Out of 152 oral drugs (including 136 drugs approved in Japan, US or both), type I nonlinearity (in which systemic drug exposure increases in a more than dose-proportional manner) was noted with 82 drugs (54%), among which 58 drugs were identified as CYP3A substrates based on public information.

Correction to: Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers.

There was a miscalculation of coproporphyrin I AUC in the published article (Volume 35, Number 7). After the correction of AUC, AUC ratio and R-square were re-calculated. Then, following corrections were made in the abstract, the body, Fig.

Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers.

Purpose: To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration-time profiles among OATP1B substrates drugs and endogenous substrates.

Methods: Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.

A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions.

Purpose: To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs.

Methods: A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600 mg, p.

Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.

Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase.

Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development.

Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration.