Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle
نویسندگان
چکیده
Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.
منابع مشابه
Corrigendum: Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle
متن کامل
Role of T-Type Amino Acid Transporter TAT1 (S1C 16a 10) in Aromatic Amino Acid Homeostasis
TAT1 (T-type amino acid transporter 1), also known as SLC16A10 (solute carrier family 16, member 10), aromatic amino acid transporter 1, MCT10 (mono carboxylate transporter 10) or PRO0813, is a 515 amino acid protein that belongs to the monocarboxylate porter family. It is a uniporter, which is a Na+-independent transporter of aromatic amino acids (AAA) such as tryptophan, tyrosine, and phenyla...
متن کاملHistochemical and immunohistochemical investigation of guanase and nedasin in human tissues.
Guanase is known as an enzyme released from the liver. Recently, cloning and sequencing of the guanase gene were reported. In addition, almost simultaneously, it was reported that an unknown protein that binds to neuronal and endocrine lethal(1)-discs large (NE-dlg), one of the membrane-associated guanylate kinase homologues (MAGUK) family proteins involved in synaptic connection between neuron...
متن کاملDapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule.
Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we deve...
متن کاملNCC27, a homolog of intracellular Cl- channel p64, is expressed in brush border of renal proximal tubule.
NCC27, a 27-kDa homolog of the intracellular chloride channel p64, was recently described as a chloride channel in nuclear membrane. We probed human Northern blots for NCC27 and found an ∼1.7-kb message in all tissues examined, including kidney, the transcript being most abundant in heart and skeletal muscle. NCC27-specific antisera was raised to a COOH-terminal peptide derived from the NCC27 c...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 7 شماره
صفحات -
تاریخ انتشار 2017