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Respiratory, endocrine, cardiac, and renal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Urine formation starts by the ultrafiltration of plasma through the glomerular capillary wall [1]. Reabsorption of filtered solutes is achieved by active or passive transport across the tubular cell membranes, using a transcellular or a paracellular route. Primary active transport requires a source of metabolic energy, provided by ATP hydrolysis. Secondary active transport of solutes along (,symport) or against (antiport) the Na+ gradient, created by its primary active transport, occurs via specific protein carriers molecules (transporters). Cell membranes contain channels allowing the rapid passage of specific ions (Na+, K+, Cl-) across cellular membranes [1].
The cell and tissues
Published in Peate Ian, Dutton Helen, Acute Nursing Care, 2020
This energy is supplied by ATP, which loses a phosphate group to become adenosine diphosphate (ADP), with the release of energy. This type of transport is involved in moving electrolytes against their concentration gradients, e.g., returning potassium to the cell and removing sodium from the cell to the interstitial fluid. This process is known as primary active transport.
Cell Components and Function
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Primary active transport utilizes energy (ATP) to move substances against their electrochemical gradients at a faster rate. Active transporting membranes contain ATPase which breaks down ATP to liberate energy. An example of this is the Na+/K+ pump, a membrane protein with ATPase activity. By splitting ATP, it is alternately phosphorylated (with high affinity for Na+ and low affinity for K+) and dephosphorylated (high K+ affinity and low Na+ affinity). The exchange ratio of Na+ to K+ is 3:2; 3 Na+ are pumped out for every 2 K+ moving in. It is not responsible for the resting membrane potential (RMP). The RMP is caused by the concentration gradients of K+ and Na+ across the membrane that are maintained by the activity of the Na+/K+ pump and the membrane impermeability to Na+. The metabolic cost of the Na+/K+ pump is high and accounts for a large part of the resting oxygen consumption of cells.
Differential interactions of carbamate pesticides with drug transporters
Published in Xenobiotica, 2020
Nelly Guéniche, Arnaud Bruyere, Mélanie Ringeval, Elodie Jouan, Antoine Huguet, Ludovic Le Hégarat, Olivier Fardel
Drug transporters mediate the passage of xenobiotics across membranes, especially the plasma membrane. They belong to the solute carrier (SLC) or the ATP-binding cassette (ABC) transporter subfamilies (Giacomini et al., 2010). SLC transporters are commonly implicated in drug uptake into cells through facilitated diffusion or secondary active transport, whereas ABC transporters act as efflux pumps through primary active transport. Transporters are now well-recognised as playing a major role in the different steps of pharmacokinetics, including intestinal absorption, distribution across blood–tissue barriers and biliary and renal elimination (Ayrton & Morgan, 2001; Konig et al., 2013). Inhibition of their activity by some drugs, called “perpetrators”, can cause drug–drug interactions due to altered pharmacokinetics profile of co-administrated drugs substrates for the inhibited transporters and termed “victims” (Liu, 2019). This may also trigger adverse toxic effects, due to inhibition of endogenous substrate transport (Nigam, 2015).
Efflux proteins at the blood–brain barrier: review and bioinformatics analysis
Published in Xenobiotica, 2018
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G. Patching
A 3.8-Å X-ray crystal structure of mouse P-gp in an inward-open conformation was originally solved through multi-wavelength anomalous dispersion (MAD) phasing (PDB 3G5U) (Aller et al., 2009) and this was later refined through single-wavelength anomalous dispersion (SAD) phasing (PDB 4M1M) (Li et al., 2014) (Figure 2A). Mouse P-gp shares 87% sequence identity with human P-gp. The overall structure of mouse P-gp is arranged as two “halves” with pseudo two-fold molecular symmetry with two cytoplasmic nucleotide-binding domains (NBDs) separated by ∼30 Å. The structure contains two bundles of six helices (TMs 1-3, 6, 10, 11 and TMs 4, 5, 7-9, 12) and has a large internal cavity open to both the cytoplasm and the inner leaflet of the membrane. Two portals formed by TMs 4/6 and 10/12 provide access routes for hydrophobic molecules directly from the membrane. The putative drug-binding pocket comprises mostly hydrophobic and aromatic residues and the volume of the internal cavity within the lipid bilayer is ∼6000 Å3, large enough for the simultaneous accommodation of at least two compounds. Two additional structures with cyclic hexapeptide inhibitors [cyclic-tris-(R)-valineselenazole (QZ59-RRR) and cyclic-tris-(S)-valineselenazole (QZ59-SSS)] bound to the internal cavity were also solved to 4.4 and 4.35 Å, respectively (PDB 3G60 and 3G61) revealing specific amino acid residues involved in drug recognition (Aller et al., 2009). The 46 residues in the drug translocation pathway of P-gp are conserved with 96% identity in those from mouse and human. The composition of these residues suggests that a significant proportion of drug-protein interactions are electrostatic, including cation–π, CH–π or π–π recognition (Li et al., 2014). The putative mechanism of substrate and drug efflux by P-gp (Figure 2B) involves partitioning of substrate into the bilayer from outside of the cell to the inner leaflet from where it enters the internal drug-binding pocket through an open portal. Residues in the drug-binding pocket interact with substrate in the inward facing conformation. ATP binds to the NBDs and undergoes hydrolysis to produce ADP and energy. There is a concomitant large conformational change that presents the substrate and drug-binding site(s) to the outer leaflet/extracellular space for expulsion to the aqueous phase. It appears that the NBDs hydrolyse ATP in an alternating manner, but it is still not clear whether transport is driven by ATP hydrolysis or ATP binding. Nonetheless, the efflux action of P-gp follows a carrier-mediated primary active transport mechanism that unidirectionally transfers only one molecule at a time. A better understanding of the structure, substrate and inhibitor interactions and molecular mechanism of P-gp would be provided by higher resolution crystal structures of P-gp solved in different conformations (inward-open, occluded, outward-open) and in complex with a range of different ligands.