Sinusoidal Efflux

MDCK II cells (Fig. 12.3) [93], Kinetic analysis revealed that the Km value for transcellular transport (24 pM) was similar to the Km for OATP2 (34 pM) [93], Moreover, the efflux across the bile canalicular membrane was not saturated under these experimental conditions. These in vitro observations are consistent with in vivo experimental results in rats which showed that the rate-determining process for the biliary excretion of pravastatin is uptake across the sinusoidal membrane. By normalizing the expression level between the double transfectant and human hepatocytes, it might be possible to predict in vivo hepatobiliary excretion. 

Suzuki, H., Sugiyama, Y., Transport of drugs across the hepatic sinusoidal membrane sinusoidal drug influx and efflux in the liver, Semin. Liver Dis. 2000, 20, 251-263. 

NaPi-1 (SLC17A1), alternatively referred to as NPT1, was originally cloned as a transporter involved in the reabsorption of phosphate in the body. Expression of NaPi-1 in X. laevis oocytes induced saturable uptake of benzylpenicillin (189). This uptake does not depend on Na+ and H+, but on Cl- (190), and increasing extracellular concentration of chloride reduced the uptake of benzyl-penicillin (190). The substrates include faropenem, foscamet, and mevalonate, as well as benzylpenicillin (190). In contrast to the kidney, the expression is localized to the sinusoidal membrane of the liver (190). When the direction of the concentration gradient of Cl- is taken into consideration, the transport direction mediated by NaPi-1 is efflux from inside the cells to the blood and urine in the liver and kidney, respectively. 

Akita H, Suzuki H, Sugiyama Y. Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver. Pharm Res 2001 18 1119-1125. 

Figure 3. Effects of changing power density of a 147-MHz radiofrequency field, sinusoidally amplitude-modulated at 16 Hz, on 45Ca2 efflux from freshly isolated chick cerebral hemispheres. Ordinate shows mean difference (with S.E.) between exposed (Vr) and control (Vr) samples (25) ...

The authors suggested that acute sexual excitement during cocaine intoxication can cause penile erection, with impaired detumescence. Cocaine can inhibit the reuptake of noradrenaline (by blocking transport in presynaptic sympathetic neurons), thus preventing sinusoidal contraction and the efflux of penile blood. 

Recently, some M RP family transporters such as MRP1,3,4, and 6 are located on the basolateral membrane and involved in the sinusoidal efflux of certain compounds... 

FIGURE 34.6 Distribution of the main drag ABC (green) and SLC (pink) transporters on the basolateral (sinusoid) and apical (bile canaliculus) membranes of the human hepatocytes. SLC transporters at the basolateral membrane mainly define active hepatic uptake whereas ABC transporters at the basolateral and bile canaliculus membranes efflux drugs and their metabolites in blood or bile, respectively. 

The activity of the sinusoidal GSH carrier is also influenced by the thiol-disulphide status [77]. Thiol oxidation favours inward transport by inhibiting efflux and consequently changes the direction of GSH transport through this... 

MRP3 is a basolateral transporter that is expressed in the liver, intestine, and kidney. This protein is believed to play a role in the movement of drugs from the cell to the blood. Under cholestatic conditions, MRP3 is upregulated in the liver, suggesting a role in the removal of toxic organic anions via sinusoidal efflux from the hepatocyte. 

In this equation, PSn iux and PSeeflux are terms describing the membrane permeability of drug across the sinusoidal membrane of the hepatocyte for influx (blood — cytoplasm) and efflux (cytoplasm blood). These processes are mediated by membrane transporters. CIh.int represents the intrinsic clearance for metabolism and biliary excretion of drug (also transporter-driven). 

Sinusoidal efflux >>> intrinsic clearance (PSeeflux >>> Cliimi)... 

Following uptake across the basolateral membrane into the cytosol, drug disposition can proceed by one of several paths, most notably biotransformation. Additionally, drug and/or formed metabolites may be excreted across the canalicular membrane into bile (described later), or may be transported back into the circulation (sinusoidal membrane efflux) with subsequent renal excretion. 

Cholestasis is a condition characterized by impaired flow of bile, due to physical obstruction of the biliary tree or decreased bile secretion by the liver. Cholestasis produces alterations of enzyme activity in the liver (cytochrome P450) as well as altered transporter expression, with associated effects on drug clearance. As discussed previously, cholestasis can occur through inhibition of the canalicular membrane transporter, BSEP. In response to cholestasis, however, the liver has adaptive mechanisms to minimize cellular accumulation of toxic bile salts. These include upregulation of MRP3 to increase sinusoidal efflux, and downregulation of Na -taurocholate cotransporting polypeptide (NTCP), which mediates bile salt uptake from the blood to the liver. 

Transporters are involved in biliary and renal excretions that are the two common routes of drug elimination. In the liver, a drug is first taken up into hepatocytes, then either secreted back to the systemic circulation or excreted to the bile in an intact form or as metabolites via Phase I and/or Phase II enzymes. Given the involvement of transporters in both uptake at the sinusoidal membrane and efflux at the sinusoidal and canulicular membranes (Fig. 6.1c), the hepatic clearance can be expressed based on well-stirred model as the following equation (Shitara et al., 2005 Yamazaki et al., 1996) ... 

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