Hepatobiliary transport mechanisms have been identified to play a significant role in determining the systemic clearance for a number of widely prescribed drugs and an increasing number of new molecular entities (NMEs). While determining the pharmacokinetics, drug transporters also regulate the target tissue exposure and play a key role in regulating the pharmacological and/or toxicological responses. Consequently, it is of great relevance in drug discovery and development to assess hepatic transporter activity in regard to pharmacokinetic and dose predictions and to evaluate pharmacokinetic variability associated with drug-drug interactions (DDIs) and genetic variants. Mechanistic predictions utilizing physiological-based pharmacokinetic modeling are increasingly used to evaluate transporter contribution and delineate the transporter-enzyme interplay on the basis of hypothesis-driven functional in vitro findings. Significant strides were made in the development of in vitro techniques to facilitate characterization of hepatobiliary transport. However, challenges exist in the quantitative in vitro-in vivo extrapolation of transporter kinetics due to the lack of information on absolute abundance of the transporter in both in vitro and in vivo situations, and/or differential function in the holistic in vitro reagents such as suspended and plated hepatocytes systems, and lack of complete mechanistic understanding of liver model structure. On the other hand, models to predict transporter-mediated DDIs range from basic models to mechanistic static and dynamic models. While basic models provide conservative estimates and are useful upfront in avoiding false negative predictions, mechanistic models integrate multiple victim and perpetrator drugs parameters and are expected to provide quantitative predictions. The aim of this paper is to review the current state of the model-based approaches to predict clinical pharmacokinetics and DDIs of drugs or NMEs that are substrates of hepatic transporters.

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A previously developed physiologically based pharmacokinetic model for hepatic transporter substrates was extended to an organic anion transporting polypeptide substrate, telmisartan. Predictions used in vitro data from sandwich culture human hepatocyte and human liver microsome assays. We have developed a novel method to calibrate partition coefficients (Kps) between nonliver tissues and plasma on the basis of published human positron emission tomography (PET) data to decrease the uncertainty in tissue distribution introduced by in silico-predicted Kps. With in vitro data-predicted hepatic clearances, published empirical scaling factors, and PET-calibrated Kps, the model could accurately recapitulate telmisartan pharmacokinetic (PK) behavior before 2.5 hours. Reasonable predictions also depend on having a model structure that can adequately describe the drug disposition pathways. We showed that the elimination phase (2.5-12 hours) of telmisartan PK could be more accurately recapitulated when enterohepatic recirculation of parent compound derived from intestinal deconjugation of glucuronide metabolite was incorporated into the model. This study demonstrated the usefulness of the previously proposed physiologically based modeling approach for purely predictive intravenous PK simulation and identified additional biologic processes that can be important in prediction.

Shewanella species grow in widely disparate environments and play key roles in elemental cycling, especially in environments with varied redox conditions. To obtain a system-level understanding of Shewanella's robustness and versatility, the complex interplay of cellular growth, metabolism, and transport under conditions of limiting carbon sources, energy sources, and electron acceptors must be elucidated. In this paper, population-level taxis of Shewanella oneidensis MR-1 cells in the presence of a rate-limiting, insoluble electron acceptor was investigated. A novel mechanism, mediated energy taxis, is proposed by which Shewanella use riboflavin as both an electron shuttle and an attractant to direct cell movement toward local sources of insoluble electron acceptors. The cells secrete reduced riboflavin, which diffuses to a nearby particle containing an insoluble electron acceptor and is oxidized. The oxidized riboflavin then diffuses away from the particle, establishing a spatial gradient that draws cells toward the particle. Experimental and modeling results are presented to support this mechanism. S. oneidensis MR-1 cells inoculated into a uniform dispersion of MnO(2) particles in dilute agar exhibited taxis outward, creating a clear zone within which riboflavin was detected by mass spectrometry. Cells inoculated into dilute agar containing oxidized riboflavin similarly exhibited taxis, rapidly forming an expanding zone of reduced riboflavin. A mathematical model based on the proposed mechanism was able to predict experimental trends, including how concentrations of riboflavin and insoluble electron acceptors (e.g., MnO(2)) affected tactic cell migration.

The photochromic properties of dihydropyrenes have been substantially improved by making use of density functional theory (DFT) activation barrier calculations, which suggested that the di-isobutenylcyclophanediene 15' should have a significant barrier to thermal isomerization to the dihydropyrene (DHP) 15, which itself should resist isomerization involving migration of the internal groups to the rearranged dihydropyrene 9 (X = -CH═C(Me)(2)). As a result of these calculations, the synthesis of the colorless cyclophanediene (CPD) 15' was undertaken and achieved from the dinitrile 28 in four steps in 37% overall yield %. The cyclophanediene 15' thermally isomerized to the dihydropyrene 15 at 100 °C with t(1/2) = 4.5 h, giving an extrapolated 20 °C t(1/2) of ∼16 y, consistent with the DFT calculations. No evidence for [1,5]-sigmatropic rearrangement in to 9 (X = -CH═C(Me)(2)) was observed on heating to 130 °C. The ring-opening isomerization quantum yields (ϕ(open)) for DHP 15 in to CPD 15' were determined in cyclohexane to be 0.12 ± 0.01, which is three times greater than for the benzoDHP 1. Friedel-Crafts naphthoylation of 15 gave 70% of purple 32, which in toluene showed the largest photochemical ring-opening isomerization quantum yields (ϕ(open)) of 0.66 ± 0.02 for any known dihydropyrene, ∼nine times greater than 1 in toluene. The thermal closing of 32' to 32, although faster than for 15', gave a useful extrapolated t(1/2) of ∼2 y at 20 °C.