Active secretion transport

X. Liu, and L. Z. Benet. Contributions of saturable active secretion, passive transcellular, and paracellular diffusion to the overall transport of furosemide across adenocarcinoma (Caco-2) cells,/. Pharm. Sci. 2002,... 

In the transport assays, the permeability of a compound in both absorption and secretion directions is measured using polarized epithelial cells that constitutively express high levels of P-gp (e.g. Caco-2) or have been transfected with the gene for a specific P-gp (e.g. MDR1-transfected MDCK or LLC-PK1 cells). Since P-gp is expressed on the apical membrane, ratios ofbasolateral-to-apical (B —> A) permeability versus apical-to-basolateral (A —> B) permeability greater than 1 may indicate an active efflux transport process. Bidirectional permeability measurements can also be performed in the presence of a specific P-gp inhibitor. Thus, apical-to-basolateral permeability increases and basolateral-to-apical permeability decreases such that... 

Apart from glomerular filtration (B), drugs present in blood may pass into urine by active secretion. Certain cations and anions are secreted by the epithelium of the proximal tubules into the tubular fluid via special, energyconsuming transport systems. These transport systems have a limited capacity. When several substrates are present simultaneously, competition for the carrier may occur (see p. 268). 

Responses to activation of the parasympathetic system. Parasympathetic nerves regulate processes connected with energy assimilation (food intake, digestion, absorption) and storage. These processes operate when the body is at rest, allowing a decreased tidal volume (increased bronchomotor tone) and decreased cardiac activity. Secretion of saliva and intestinal fluids promotes the digestion of foodstuffs transport of intestinal contents is speeded up because of enhanced peristaltic activity and lowered tone of sphincteric muscles. To empty the urinary bladder (micturition), wall tension is increased by detrusor activation with a concurrent relaxation of sphincter tonus. 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

The principal determinants of lOP are the rate of aqueous fluid production by the ciliary epithelium and the rate of fluid drainage (outflow) in the canal of Schlemm. Aqueous fluid production involves passive, near-isosmolar fluid secretion driven by active salt transport across the ciliary epithelium. Ion and solute transporters have been identified on pigmented and non-pigmented layers of the ciliary epithelium that probably facilitate active solute secretion. Aqueous fluid drainage is believed to involve pressure-driven bulk fluid flow in the canal of Schlemm, as well as fluid movement through the sclera by seepage across the ciliary muscle and supraciliary space. 

Factors analogous to those affecting gut absorption also can affect drug distribution and excretion. Any transporters or metabolizing enzymes can be taxed to capacity—which clearly would make the kinetic process nonlinear (see Linear versus Nonlinear Pharmacokinetics ). In order to have linear pharmacokinetics, all components (distribution, metabolism, filtration, active secretion, and active reabsorption) must be reasonably approximated by first-order kinetics for the valid design of controlled release delivery systems. 

A second important factor affecting the kidneys sensitivity to chemicals is its ability to concentrate the tubular fluid and, as a consequence, as water and salts are removed, to concentrate any chemicals it contains. Thus a nontoxic concentration in the plasma may be converted to one that is toxic in the tubular fluid. The transport characteristics of the renal tubules also contribute to the delivery of potentially toxic concentrations of chemicals to the cells. If a chemical is actively secreted from the blood into the tubular fluid, it will accumulate initially within the cells of the proximal tubule or, if it is reabsorbed from the tubular fluid, it will pass into the cells in relatively high concentration. 

The columnar epithelial cells of the intestinal mucosa actively absorb and secrete extracellular ions, nutrients, and water. The active secretion of ions by these cells with an accompanying fluid flux acts to dilute and purge microorganisms or toxins in the bowel promotes the transfer of secretory immunoglobulin A, antimicrobial defensin peptides, and mucin into intestinal mucus and the gut lumen and, by affecting intraluminal pH, may alter the growth characteristics of enteric microflora [121]. Mucosal secretion is modulated by several enteric neurotransmitters, as well as inflammatory mediators released by mucosal mast cells that may affect transport indirectly through their ability to stimulate enteric neurons [122],... 

Most studies of the local actions of opioids on the intestinal mucosa have utilized muscle-stripped sheets of ileal mucosa with attached submucosa mounted in Ussing flux chambers. Peptidase-resistant enkephalin derivatives such as DPDPE decrease short-circuit current, an electrical measure of active transepithelial ion transport, across isolated mucosal sheets from the guinea pig ileum [46,127,128], rabbit ileum [129-131], mouse jejunum [132], and pig distal jejunum/ileum [133]. This effect, which occurs after the application of opioid agonists to the serosal aspect of epithelial sheets, is due to an increase in electroneutral salt absorption and a decrease in electrogenic chloride secretion [46,132,133], In contrast to enkephalin derivatives, opiate alkaloids have limited effects on active transepithelial transport of ions [69]. Pretreat-... 

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