Although the cerebral accumulation of guanidinoacetate (GAA) contributes to neurological complications in S‐adenosylmethionine:guanidinoacetate N‐methyltransferase (GAMT) deficiency, how GAA is abnormally distributed in the brain remains unknown. The purpose of this study was to investigate the transport of GAA across the blood–brain barrier (BBB) and in brain parenchymal cells in rats. [14C]GAA microinjected into the rat cerebrum was not eliminated from the brain, implying the negligible contribution of GAA efflux transport across the BBB. In contrast, in vivo analysis and an uptake study by TR‐BBB cells, a rat in vitro BBB model, revealed that GAA was transported from the circulating blood across the BBB most likely via a creatine transporter (CRT). Although CRT at the BBB is almost saturated by endogenous creatine under physiological conditions, the creatine level in the blood significantly decreases in GAMT deficiency. This might lead to the increase of CRT‐mediated blood‐to‐brain transport of GAA at the BBB. Furthermore, [14C]GAA was taken up by brain parenchymal cells in a concentrative manner most likely via taurine transporter and CRT. These characteristics of GAA transport across the BBB and in the brain parenchymal cells could be the key factors that facilitate GAA accumulation in the brains of patients with GAMT deficiency.

Although the level of prostaglandin (PG) D 2 in cerebrospinal fluid (CSF) affects the action of D-type prostanoid receptors that promote physiological sleep, the regulatory system of PGD 2 clearance from the CSF is not fully understood. The purpose of this study was to investigate PGD 2 elimination from the CSF via the blood-CSF barrier (BCSFB). The in vivo PGD 2 elimination clearance from the CSF was 16-fold greater than that of inulin, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGD 2 . The characteristics of PGD 2 uptake by isolated choroid plexus were, at least partially, consistent with those of PG transporter (PGT) and organic anion transporter 3 (OAT3). Studies using an oocyte expression system showed that PGT and OAT3 were able to mediate PGD 2 transport with a Michaelis-Menten constant of 1.07 and 7.32 M, respectively. Reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that PGT was localized on the brush-border membrane of the choroid plexus epithelial cells. These findings indicate that the system regulating the PGD 2 level in the CSF involves PGT-and OAT3-mediated PGD 2 uptake by the choroid plexus epithelial cells, acting as a pathway for PGD 2 clearance from the CSF via the BCSFB.

Manufacturing parameters may have a strong impact on the dissolution and disintegration of solid dosage forms. In line with process analytical technology (PAT) and quality by design approaches, computer-based technologies can be used to design, control, and improve the quality of pharmaceutical compacts and their performance. In view of shortcomings of computationally intensive finite-element or discrete-element methods, we propose a modeling and simulation approach based on numerical solutions of the Noyes-Whitney equation in combination with a cellular automata-supported disintegration model. The results from in vitro release studies of mefenamic acid formulations were compared to calculated release patterns. In silico simulations with our disintegration model showed a high similarity of release profile as compared to the experimental evaluation. Furthermore, algorithmically created virtual tablet structures were in good agreement with microtomography experiments. We conclude that the proposed computational model is a valuable tool to predict the influence of material attributes and process parameters on drug release from tablets.