ReviewTransporters as a determinant of drug clearance and tissue distribution
Introduction
Drug elimination in the liver consists of the following processes: (1) hepatic uptake, (2) metabolism and/or (3) biliary excretion (Pang and Rowland, 1977, Pang and Gillette, 1978, Yamazaki et al., 1996a, Shitara et al., 2005). In addition, (4) sinusoidal efflux from the inside of the cell to the blood also determine the hepatic elimination rate. Among these processes, drug transporters are involved in uptake, sinusoidal efflux and biliary excretion (Meier et al., 1997, Kullak-Ublick et al., 2000, van Montfoort et al., 2003, Giacomini and Sugiyama, 2005). Recently, molecular cloning of drug transporters has greatly helped the characterization of the mechanism of drug elimination in the liver (Hagenbuch and Meier, 2003, Keppler and Konig, 2000, Mizuno et al., 2003). It should be noted that hepatic uptake and biliary excretion determine the drug concentration in the liver, and they may affect the pharmacological effects and/or toxic side effects (Giacomini and Sugiyama, 2005). Thus, drug transporters are also a determinant of pharmacological effects and/or side effects for drugs whose target is the liver.
In the kidney, drug clearances are determined by: (1) glomerular filtration, (2) tubular secretion and (3) reabsorption (Inui et al., 2000a, Inui et al., 2000b, Dresser et al., 2001). As glomerular filtration is simply the ultrafiltration of drugs not bound to plasma proteins, no transporters are involved. Transporters are mainly involved in tubular secretion and reabsorption (Koepsell and Endou, 2004, Sekine et al., 2000, Wright and Dantzler, 2004). Several active transport mechanisms have been reported in the proximal tubules and these are involved in secretion. Reabsorption is sometimes mediated by transporters although many drugs are reabsorbed only by passive diffusion depending on a high drug concentration gradient across the blood and nephron, which is caused by reabsorption of water back into the plasma.
Orally administered drugs firstly pass through the intestine and subsequently appear in the portal blood. This intestinal absorption affects the drug concentration in the circulating blood. Moreover, the intestine functions as a barrier to xenobiotics (Wacher et al., 2001, Zhang and Benet, 2001). In these processes, transporters in intestine play important roles (Ganapathy and Leibach, 1982, Amidon and Lee, 1994, Tsuji and Tamai, 1996, Terada and Inui, 2004). Transporters in the liver, kidney and intestine are illustrated in Fig. 1.
Transporters in other tissues are also determinants of the distribution of drugs to the target organs for the pharmacological effects and/or adverse reactions. Since the distribution volume of drugs to the brain is generally low, transporters in the brain do not affect the plasma concentration of drugs. However, they control the drug distribution to the brain, affecting the pharmacological effects or side effects (Tamai and Tsuji, 2000, Kusuhara and Sugiyama, 2004, Kusuhara and Sugiyama, 2005).
In this manuscript, we shall focus on the transporter functions in the kidney and liver and review the mechanisms of drug elimination. We will also describe a recently developed method of analyzing transporter function by estimating the contribution of each transporter, and the use of transporter double transfectants.
Section snippets
Substrates of hepatobiliary transporters
Table 1 shows some of therapeutic drugs which are substrates of transporters in the liver. Among them, some drugs are taken up into hepatocytes, followed by metabolism while others are excreted into the bile in intact form (Stieger and Meier, 1998, Keppler and Konig, 2000, van Montfoort et al., 2003, Fujino et al., 2004a). For example, atorvastatin, a 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), is taken up into liver via transporter(s) including organic anion
The mechanism of transporter-mediated drug–drug interactions
We analyzed the mechanism of the drug–drug interaction between cerivastatin and CsA and showed that CsA inhibited the transporter (including OATP1B1)-mediated uptake with only a minimal effect on the microsomal metabolism, suggesting that this drug–drug interaction is due to the transporter-mediated uptake process (Shitara et al., 2003). The pharmacokinetics of cerivastatin is also affected by the coadministration of gemfibrozil (Backman et al., 2002). This is due to inhibition of the
The importance of the contribution of transporters
Currently, great progress is being made in the molecular cloning of transporters. These studies help to characterize the molecular mechanisms of drug transport by using transporter-expressing systems. However, the contribution of each transporter to drug transport in vivo has not yet been evaluated. Using these contributions, the uptake clearance in the transporter-expressing systems can be extrapolated to that in the tissue, and it is possible to quantitatively predict the transporter-mediated
Transport studies using double transfected cells
For transporter-mediated transcellular transport, substrates need to be taken up into cells and excreted to the opposite side via two different transporters. To evaluate the transcellular transport, transporter double transfected cells have been developed and used. In this section, analyses using these cells are described.
Double transfected cells were introduced by Cui et al. in 2001 and by Sasaki et al. in 2002 (Cui et al., 2001, Sasaki et al., 2002). They constructed OATP1B3-MRP2 and
Conclusion
This review has examined the involvement of transporters in the hepatobiliary and renal transport of drugs. In addition, we have introduced a recently developed method to evaluate the transporter-mediated transport of drugs. Until now, the number of reports of pharmacokinetic alterations caused by transporter-mediated drug–drug interactions or genetic polymorphisms in transporters is less than those involving in metabolism. However, there may be increasing numbers of reports of such
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