Incorporating Uremic Solute-mediated Inhibition of OAT1/3 Improves PBPK Prediction of Tenofovir Renal and Systemic Disposition in Patients with Severe Kidney Disease.

Background: Dose modification of renally secreted drugs in patients with chronic kidney disease (CKD) has relied on serum creatinine concentration as a biomarker to estimate glomerular filtration (GFR) under the assumption that filtration and secretion decline in parallel. A discrepancy between actual renal clearance and predicted renal clearance based on GFR alone is observed in severe CKD patients with tenofovir, a compound secreted by renal OAT1/3. Uremic solutes that inhibit OAT1/3 may play a role in this divergence.

Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system.

Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CL) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model.

Recent advances in the ontogeny of drug disposition.

Developmental changes that occur throughout childhood have long been known to impact drug disposition. However, pharmacokinetic studies in the paediatric population have historically been limited due to ethical concerns arising from incorporating children into clinical trials. As such, much of the early work in the field of developmental pharmacology was reliant on difficult-to-interpret in vitro and in vivo animal studies.

An Improved Vascularized, Dual-Channel Microphysiological System Facilitates Modeling of Proximal Tubular Solute Secretion.

A vascularized human proximal tubule model in a dual-channel microphysiological system (VPT-MPS) was developed, representing an advance over previous, single-cell-type kidney microphysiological systems. Human proximal tubule epithelial cells (PTECs) and human umbilical vein endothelial cells (HUVECs) were cocultured in side-by-side channels. Over 24 h of coculturing, PTECs maintained polarized expression of Na/K ATPase, tight junctions (ZO-1), and OAT1.

Reevaluating the role of megalin in renal vitamin D homeostasis using a human cell-derived microphysiological system.

The role of megalin in the regulation of renal vitamin D homeostasis has previously been evaluated in megalin-knockout mice and rat proximal tubule epithelial cells. We revisited these hypotheses that were previously tested solely in rodent models, this time using a 3-dimensional proximal tubule microphysiological system incorporating primary human proximal tubule epithelial cells. Using this human cell-derived model, we confirmed that 25OHD3 is transported into the human proximal tubule epithelium via megalin-mediated endocytosis while bound to vitamin D binding protein.

Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D-3--Sulfate, a Major Circulating Vitamin D Metabolite in Humans.

Metabolism of 25-hydroxyvitamin D (25OHD) plays a central role in regulating the biologic effects of vitamin D in the body. Although cytochrome P450-dependent hydroxylation of 25OHD has been extensively investigated, limited information is available on the conjugation of 25OHD In this study, we report that 25OHD is selectively conjugated to 25OHD-3--sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD, 25OHD-3--sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route.

Potent inhibition of human organic cation transporter 2 (hOCT2) by β-carboline alkaloids.

1. Beta-carbolines are indole alkaloids with a wide range of pharmacological and toxicological activities. Beta-carbolines are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a known substrate of organic cation transporters (OCTs).

Development of a microphysiological model of human kidney proximal tubule function.

The kidney proximal tubule is the primary site in the nephron for excretion of waste products through a combination of active uptake and secretory processes and is also a primary target of drug-induced nephrotoxicity. Here, we describe the development and functional characterization of a 3-dimensional flow-directed human kidney proximal tubule microphysiological system. The system replicates the polarity of the proximal tubule, expresses appropriate marker proteins, exhibits biochemical and synthetic activities, as well as secretory and reabsorptive processes associated with proximal tubule function in vivo.