ND, not determined; SPNT, sodium-dependent purine nucleoside transporter.

ND, not determined; SPNT, sodium-dependent purine nucleoside transporter.

intestine and kidney, where it is less than 1% of that of OCT2. There is enough OCT1 in the kidneys of rats, mice, and rabbits for it to play a significant role in substrate transport. OCT2 is mainly found in the kidneys of rats and humans. The amount of OCT2 in the kidney depends on gender and age. The kidneys of males contain more oct2 mRNA and protein than do those of females, whereas the concentrations of OCT2 in young male and female rats are similar.87 Although the physiological relevance of this gender dimorphism is unknown, it might be responsible for differences in the renal elimination of OCs and responses and sensitivity to drugs. OCT2 is also present at the choroid plexus and in various dopamine-rich regions of the brain (substantia nigra, nucleus accumbens, and striatum), where it might act as a 'background' transporter in the removal of monoamine neurotransmitters that have escaped reuptake by high-affinity monoamine transporters.83

OCT3, unlike OCT1 and OCT2, is much more widely distributed. hOCT3 mRNA has been detected in the aorta, skeletal muscle, prostate, adrenal gland, and placenta.88 OCT3 is also abundant in the mammalian brain, where it has been identified as an extraneuronal monoamine transporter like OCT2.89 OCT3 also plays a very limited role in the transport of type 1 OCs (TEA) in the human and rodent kidney. Nevertheless, OCT3 seems to play a significant role in the handling of amantadine, a putative dopaminergic compound, by the rat and rabbit kidneys.86

The quantitative significance of the OCTs in drug pharmacokinetics was clearly established in studies with mice lacking the three Octs. All three knockout strains are viable, fertile, and display no physiological abnormalities.83 However, the knockout of Octs markedly affects the pharmacokinetics of OC substrates. For example, the knockout of both Oct1 and Oct2 transporters eliminates the renal tubular secretion of TEA and reduces the hepatic uptake and clearance of TEA by about 80% in the Oct1 knockout mice due to the lack of Oct1 at the sinusoidal membrane of the hepatocytes.89 The intestinal secretion of TEA is reduced by about 50%, indicating that Oct1 also mediates the basolateral uptake of TEA into enterocytes. Similar observations were made with the liver uptake of several biguanides (metformin and buformin); these antidiabetes drugs are sometimes responsible for lactic acidosis. The accumulation of metformin in the liver was

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