Читать книгу Drug Transporters - Группа авторов - Страница 36

In vivo studies in mice in which individual transporters have been removed genetically (knockout (KO) mice) provide valuable insights in potential physiologic and biomedical functions of OCTs. However, species differences between OCTs of humans and rodents impose limitations on the ability to apply conclusions obtained from the mouse experiments to humans. Oct1 knockout mice are viable and fertile, with no obvious physiological abnormalities when compared with their wild‐type littermates, suggesting that Oct1 has minimal impact on normal physiology [24]. However, at the biochemical level, disruption of OCT1 in mice affects both lipid and glucose metabolism by reducing the hepatic uptake of thiamine [2]. Additionally, disruption of Oct1 in mice has significant impact on the disposition of organic cations. For example, when administered the prototypical organic cation, TEA, Oct1 ^−/− mice show significantly reduced uptake of TEA into the liver. In accordance with reduced hepatic uptake of TEA, biliary excretion is lower in Oct1 ^−/− mice [24]. Additionally, direct intestinal excretion of TEA is reduced by approximately 50%. In addition to TEA, Oct1 ^−/− mice have similar decreases in hepatic uptake of other OCT1 substrates (i.e., MPP⁺ and meta‐iodobenzylguanidine (MIBG)) [24].

In addition to pharmacokinetic effects, knockout of Oct1 in mice can have implications for prescription drugs, exemplified by metformin, an anti‐hyperglycemic prescription medication used as a first‐line treatment for Type 2 diabetes. Despite similar pharmacokinetic profiles between Oct1 ^−/− and wild‐type mice, Oct1 ^−/− mice showed greater than 30‐fold decrease in metformin uptake into liver, the site of action for metformin, compared with wild‐type littermates [25]. Further studies investigated the role of Oct1 in the development of metformin‐induced lactic acidosis, a leading toxicity from this drug. A significant increase in serum lactic acid concentration was observed after administration of metformin to wild‐type mice, but only slight elevations in serum lactate were seen in Oct1 −/− mice [26]. Taken together, these results suggest that Oct1‐mediated metformin transport is a limiting step in metformin uptake into liver, and that the lactic acidosis induced by metformin is related to the availability of the drug to its target organ. Recent studies have demonstrated large effects of knocking out Oct1 on the hepatic uptake and clearance of sumatriptan and fenoterol, and lesser effects on ondansetron [27].

TABLE 2.2 Selected substrates and inhibitors of the major organic cation and zwitterion transporters, OCT1‐3 and OCTN1‐2 [6, 16, 17]

Transporter	Model substrates	Substrates	Model inhibitors	Inhibitors
OCT1	MPP+, TEA, ASP+, metformin	Endogenous: serotonin, acylcarnitines, choline, acetylcholine, creatinine, agmatine, thiamine Exogenous: acyclovir, quinidine, quinine, thiamine, sumatriptan, ondansetron, morphine	Quinidine, verapamil	Exogenous: atropine, abacavir, tenofovir, zidovudine, spironolactone, ondansetron, quinine, midazolam
OCT2	TEA, ASP+, MPP+, NBD‐MTMA, metformin	Endogenous: creatinine, choline, serotonin, dopamine, histamine Exogenous: amphetamine, cisplatin, cimetidine, phenformin	Quinidine, cimetidine	Endogenous: testosterone Exogenous: doxepin, zolpidem, ritonavir, imipramine, tramadol, tacrine, olanzapine
OCT3	MPP+, ASP+, metformin	Endogenous: creatinine, agmatine, dopamine, progesterone, testosterone Exogenous: atropine, prazosin, cimetidine, verapamil, nicotine	Corticosterone	Endogenous: progesterone, B‐estradiol, corticosterone Exogenous: verapamil, carvedilol, imipramine, cimetidine, metformin
OCTN1	L‐ergothioneine, TEA	Endogenous: L‐ergothioneine, L‐carnitine, acetylcholine Exogenous: cytarabine, amisulpride, ethambutol, ipratropium, gapapentin	TEA	Endogenous: L‐carnitine, acetylcarnitine, choline, acetylcholine, gamma‐butyrobetaine Exogenous: carvedilol, flecainide, lidocaine, verapamil, mitoxantrone, dipyridamole, doxorubicin
OCTN2	L‐carnitine	Endogenous: L‐carnitine, acetyl‐L‐carnitine, choline Exogenous: D‐carnitine, mildronate, ipratropium, etoposide, amisulpride	TEA, verapamil	Endogenous: L‐carnitine, acetylcarnitine Exogenous: clozapine, emetine, vinblastine, omeprazole, verapamil, B‐lactam antibiotics

Abbreviations:

MPP⁺ : N‐methyl‐4‐phenylpyridinium.

TEA: tetraethylammonium.

ASP⁺ : 4‐(4‐(diethylamino)styryl)‐N‐methylpyridinium.

NBD‐MTMA: N,N,N‐trimethyl‐2‐[methyl(7‐nitrobenzo[c][l,2,5]oxadiazol‐4‐yl)amino]ethanaminium.