Apical clearance

It is also important to predict the in vivo biliary excretion clearance in humans, and for this purpose MDCK II cell lines expressing both uptake and efflux transporters may be used (Fig. 12.3) [92, 93]. It has been shown that MRP2 is expressed on the apical membrane, whereas OATP2 and 8 are expressed on the basolateral membrane after cDNA transfection (Fig. 12.3) [92, 93]. The transcellular transport across such double-transfected cells may correspond to the excretion of ligands from blood into bile across hepatocytes. Indeed, the vectorial transport from the basal to apical side was observed for pravastatin only in OATP2- and MRP2-expressing... 

In vitro stndies have shown that there are distinct transport systems for both baso-lateral and apical uptake of nicotine (Takami et al. 1998). Nicotine has been shown to be actively transported by kidney cells, most likely by the organic ion transporter OCT2 (Zevin et al. 1998 Urakami et al. 1998). Cimetidine decreases renal clearance of nicotine by 47% in nonsmoking volunteers (Bendayan et al. 1990). This is consistent with the inhibition of basolateral uptake by cimetidine detected in vitro. Mecamylamine reduces renal clearance of nicotine in smokers dosed with intra-venons nicotine when urine is alkalinized, but not when nrine is acidified (Zevin et al. 2000). 

By virtue of their size and charge, peptide molecules are not the ideal candidates for transfer into the systemic circulation following instillation in the nose. Among the many barriers to absorption that must be overcome are mucociliary clearance, extracellular enzymatic destruction, the lipophilic bilayer membrane of nasal epithelial cells, the potential for nasal epithelial cells to degrade any peptide molecules that cross the lipid bilayer, and the potential to establish futile cycles of endocytosis and exocytosis on the apical surface of polarized epithelial cells. Indeed, in the face of these multiple barriers, it seems all the more remarkable that any substantial absorption of peptide drugs from the nose has ever been observed. Despite these barriers, recent... 

Figure 6 Directional transport of pravastatin in Oatplb2/Mrp2 double transfectants in the apical direction (A), and comparison of in vivo biliary excretion clearance and in vitro transcellular transport clearance across the double transfectant (B). (A) Transcellular transport across the monolayers of MDCK II cells was determined in the basal-to-apical and the opposite direction. (B) The x axis represents CLint determined in vitro multiplied by /B and the scaling factor, and the y axis represents the in vivo biliary clearance defined for the blood ligand concentrations. The symbol ( ) represents data whose x axis values were corrected for the scaling factor (a = 17.9). The solid line represents the theoretical curve, and the symbol (o), the observed data. Source From Ref. 59.

Fig. 5.1 Pathogenesis of Salmonella Typhimurium and Salmonella Typhi. Upon ingestion, Salmonella travel to the small intestine. The bacteria invade Microfold (M) cells and other intestinal epithelial cells through the apical surface to cause infection. (A). Salmonella Typhimurium remains localized in the small intestine and induces an inflammatory host immune response, resulting in bacterial clearance from immunocompetent individuals. (B). Salmonella Typhi escapes from intestinal epithelial cells at the basolateral surface of the intestinal epithelium, enters phagocytes, and evades the host innate immune response, resulting in systemic infection...

Second, certain nucleotide phosphonates (e.g., adefovir and cidofovir) are effective antivirals, but their use in the clinic is limited by renal toxicity. This is believed to be caused by avid uptake at the basolateral membrane of renal proximal tubule cells followed by slow transport into the urine at the apical membrane, a sequence of events that results in intracellular drug accumulation and thus toxicity. As with penicillin, the OAT family of transporters has been implicated in cidofovir uptake. Co-administration of probenecid with cidofovir has been shown to decrease renal clearance of the antiviral and reduce its nephrotoxicity, presumably through com-... 

Oxalate is excreted primarily by the kidney. Oxalate is freely filtered at the glomerulus, where its concentration is normally 1 5 pM. One of the few physiologic functions of oxalate occurs in the proximal tubule where it plays a role in transcellular reabsorption of chloride (mainly present as sodium chloride). Cl entry across the apical membrane is mediated by Cl /oxalate exchange (oxalate is recycled from the tubular lumen to the cell by oxalate/ sulfate exchange, in parallel with Na /sulfate cotransport) [4]. Early studies of renal oxalate clearance using radio-labeled oxalate showed secretion in almost all subjects studied. More recent studies using direct measurement of serum and urine... 

Figure 11.5 Vectorial transcellular transport of pravastatin, its basal-to-apical transcellular drugs in double-transfected cells, (a) The double- transport is significantly higher compared to the transfected cells expressing OATP1B1 (uptake apical-to-basal transport [177]. (b) Prediction of transporter) on the basal side and MRP2 (efflux in vivo biliary clearance of several bisubstrates of transporter) on the apical side have been rat Oatplb2 and Mrp2 from their in vitro...

FIGURE 34.8 Distribution of the main drug ABC (green) and SLC (pink) transporters on the basola-teral (peritubular fluid) and apical (glomerular filtrate) membranes of the kidney proximal tubule cells. Active secretion and reabsorption help to define the overall renal clearance of drugs and xenobiotics. 

We also examined the permeability characteristics of acyl-TGs using Caco-2 mono-layers [53]. The disappearance of acyl-TGs from the apical side of Caco-2 monolayers was estimated by dividing into degradation and permeation processes in terms of clearance. The amount of native TG transported to the basolateral side was very low due to its large degradation clearance (CLd) on the apical side. Degradation of... 

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