Summary: ABC cassette proteins1522

might be involved in high affinity transport of endoge- At the canalicular plasma membrane monoquaternarydrugs (for example, N-methyl-quinidine, N-methyl-qui-nous compounds in selected tissues in addition to theirnine) are transported in a stereospecific manner by ratrole in overall amphipathic drug clearance by the liverMdr1b and human MDR1, but not by Mdr2 [12].and other drug eliminating organs. Since the Oatps/

OATPs can remove amphipathic drugs from their albu-REFERENCESmin-binding, hepatic Oatps/OATPs complement the re-

nal drug eliminating OATs by mediating hepatic clear- 1. Burckhardt G, Wolff NA: Structure of renal organic anion andcation transporters. Am J Physiol (Renal Physiol) 278:F853–F866,ance of larger and more hydrophobic compounds. By2000virtue of their strategic presystemic localization, hepatic 2. Sekine T, Cha SH, Endou H: The multispecific organic anion

Oatps/OATPs also must be taken into consideration in transporter (OAT) family. Pflugers Arch 440:337–350, 20003. Islinger F, Gekle M, Wright SH: Interaction of 2,3-dimercapto-the modulation of “hepatic first-pass clearance” and,

1-propane sulfonate with the human organic anion transporterthus, the overall bioavailability of amphipathic drugs. hOAT1. J Pharmacol Exp Ther 299:741–747, 20014. Kobayashi Y, Hirokawa N, Ohshiro N, et al: Differential geneMichael Muller (Wageningen, The Netherlands) sum-

expression of organic anion transporters in male and female rats.marized the “molecular and functional properties of he-Biochem Biophys Res Commun 290:482–487, 2002

patic transport systems for organic cations.” Previous stud- 5. Leier I, Hummel Eisenbeiss J, Cui Y, Keppler D: ATP-dependentpara-aminohippurate transport by apical multidrug resistance pro-ies in the isolated perfused rat liver and freshly isolatedtein MRP2. Kidney Int 57:1636–1642, 2000hepatocytes have suggested that rat hepatocytes express

6. Meier PJ, Stieger B: Bile salt transporters. Annu Rev Physioldistinct transport systems for uptake of small relative 64:635–661, 2002

7. Gao B, Meier PJ: Organic anion transport across the choroidhydrophilic “type I” (system1) and “bulky” more hydro-plexus. Microsc Res Tech 52:60–64, 2001phobic “type II” (system2) organic cations. This concept 8. Gao B, Wenzel A, Grimm C, et al: Localization of organic anion

has been supported by more recent studies in heterolo- transport protein 2 in the apical region of rat retinal pigmentepithelium. Invest Ophthalmol Vis Sci 43:510–514, 2002gous expression systems indicating that system1 corre-

9. St Pierre MV, Hagenbuch B, Ugele B, et al: Characterization ofsponds to the organic cation transporter 1 (Oct1, Slc22a1) an organic anion-transporting polypeptide (OATP-B) in human

placenta. J Clin Endocrinol Metab 87:1856–1863, 2002and system2 to the organic anion transporting polypep-10. Pizzagalli F, Hagenbuch B, Stieger B, et al: Identification of atide 2 (Oatp2) [11]. Thus, certain Oatps/OATPs cannot

novel human organic anion transporting polypeptide (OATP-F)only transport organic anions, they also accept positively as a high affinity thyroxine transporter. Mol Endocrinol 2002

11. van Montfoort JE, Muller M, Groothuis GM, et al: Comparisoncharged organic compounds. However, the clear-cut dis-of “type I” and “type II” organic cation transport by organic cationtinction between “type I” and “type II” organic cation transporters and organic anion-transporting polypeptides. J Phar-

uptake systems in rat liver cannot be translated to the macol Exp Ther 298:110–115, 200112. Hooiveld GJEJ, Heegsma J, van Montfoort JE, et al: Stereoselec-human liver without modification, since overlapping or-

tive transport of hydrophilic quaternary drugs by human MDR1ganic cation transport properties were found between and rat Mdr1b P-glycoproteins. Br J Pharmacol 135:1685–1694,2002human liver OCT1 (SLC22A1) and OATP-A (SLC21A3).

ABC transporters in adverse drug reactions anddrug resistance

Chair: ERNST PETZINGER

Giessen, Germany

at the level of intestine, liver and kidney. On the otherThe last session was opened by Martin Fromm (Stutt-hand, the antibiotic rifampicin enhances P-glycoproteingart, Germany), who talked about “ABC transporters and(P-gp) expression and causes reduced plasma concentra-drug disposition.” Clinically important are, for example,tions of P-gp substrates. In addition, a widespread C3435Tdrug-drug interactions such as the enhancement of bloodmutation of P-gp has been shown to be associated withconcentrations of the heart glycoside digoxin during con-low level P-gp expression in gut and higher bioavailabilitycomitant treatment with the anti-arrhythmic drug quinidineof digoxin in Caucasians [2].[1]. The underlying mechanism is inhibition of P-glycopro-

tein mediated digoxin transport, which occurs most likely Alfred Schinkel (Amsterdam, The Netherlands)

Summary: ABC cassette proteins 1523

stressed the importance of “In vivo P-gp inhibition to cholic acid modestly up-regulates via PXR Mrp2; in addi-tion Mrp 4 is strongly up-regulated via PXR and theimprove the pharmacological behavior of HIV-proteasephenobarbital-sensitive nuclear factor CAR as well. Sinceinhibitors” such as of saquinavir and ritonavir. He showedMrp4 is present in the basolateral membrane of hepato-that combined application of ritonavir with saquinavircytes as well as in cholangiocytes, this ABC-carrier estab-increased blood levels of saquinavir by retarding its elim-lishes a detoxification pathway under high bile salt load-ination, probably primarily by inhibition of its metabo-ing, for example, during cholestasis [4].lism by the P450 protein Cyp 3A4. If an inhibitor of P-

gp was given in addition, blood and brain levels increasedREFERENCESeven further [3]. Improvements of saquinavir pharmaco-

kinetics are particularly important for fetuses from HIV- 1. Fromm MF, Kim RB, Stein CM, et al: Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the inter-infected woman, since protective drug preloading of theaction between digoxin and quinidine. Circulation 99:552–557, 1999fetuses is feasible. 2. Hoffmeyer S, Burk O, von Richter O, et al: Functional polymor-

In his lecture, John Schuetz (Memphis, Tennessee, phisms of the human multidrug-resistance gene: Multiple sequencevariations and correlation of one allele with P-glycoprotein expres-USA) presented results about the “Interactions betweension and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478,nuclear receptors, ABC transporters, and cytochromes 2000

3. Huisman MT, Smit JW, Wiltshire HR, et al: P-glycoprotein limitsP450.” He used knockout mice with deficiency in nuclearoral availability, brain, and fetal penetration of saquinavir even withtranscription factor FXR (farnesoid-X-receptor) to showhigh doses of ritonavir. Mol Pharmacol 59:806–813, 2001

that the expression of the mouse bile acid export pump 4. Schuetz EG, Strom S, Yasuda K, et al: Disrupted bile acid homeo-stasis reveals an unexpected interaction among nuclear hormone(Bsep) by bile acids is detoriated. Such mice have in-receptors, transporters, and cytochrome P450. J Biol Chem 276:creased bile acid levels in blood and overexpressed39411–39418, 2001

CYP3A11, CYP2B10 and Mrp4. This points to an impor-Reprint requests for the Symposium summary to Bruno Stieger, Ph.D.,tant role of certain cell toxic bile acids, in particular

M.D., Klinische Pharmakologie und Toxikologie, Department fur In-chenodeoxycholate and lithocholate, as gene regulators nere Medizin,UniversitatsSpital Zurich, Ramistrasse 100, CH-8091 Zu-rich, Switzerland.via FXR and also PXR (�-pregnane-X-receptor). Litho-