Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation.

Background And Objectives: Trofinetide, the first approved treatment for Rett syndrome (RTT), is primarily excreted unchanged in the urine; therefore, it is important to assess the extent to which the exposure is affected in patients with renal impairment. Pharmacokinetic modeling overcomes the challenge of dose finding in phase 1 studies that include special populations where there is the potential for increased exposure to study drug. The objectives of this phase 1 study were to evaluate trofinetide pharmacokinetics, safety, and tolerability in a population with moderate renal impairment and normal renal function.

Characterization of monocarboxylate transport in human kidney HK-2 cells.

The objectives of this study were to characterize the expression and function of monocarboxylate transporters (MCTs) in human kidney HK-2 cells and to compare the expression of MCTs in HK-2 cells to that found in human kidney. mRNA and protein expression of MCTs were determined by RT-PCR and Western analyses, respectively, while immunofluorescence staining was used to determine the membrane localization of MCT1. The driving force, transport kinetics, and inhibition of two MCT substrates, D-lactate and butyrate, were characterized in HK-2 cells.

Transport of gamma-hydroxybutyrate in rat kidney membrane vesicles: Role of monocarboxylate transporters.

Intoxication with gamma-hydroxybutyrate (GHB) is associated with coma, seizure, and death; treatment of overdoses is symptomatic. Previous studies in our laboratory have demonstrated that L-lactate and pyruvate treatment can increase the renal clearance of GHB and increase its elimination in rats, suggesting that GHB may undergo renal reabsorption mediated by monocarboxylic acid transporters (MCTs). The goals of this study were to characterize the renal transport of GHB in rats and to determine the role of MCT in its renal transport.

Choline uptake in human intestinal Caco-2 cells is carrier-mediated.

The objective of the current investigation was to examine the transport characteristics of choline, an endogenous quaternary ammonium compound, into human intestinal Caco-2 cells; the transport of choline has not been characterized in human intestine. The cellular accumulation of choline was independent of an inwardly directed Na(+) gradient and demonstrated temperature dependence and saturability. Using the initial uptake rates, choline accumulation was best characterized by a Michaelis-Menten equation and a diffusion component with a K(m) and V(max) of 110 +/- 3 micro mol/L and 2800 +/- 250 pmol/(mg protein.