[Rifaximin--a non-resorbable antibiotic with many indications in gastroenterology]. / Rifaximin - ein nicht resorbierbares Antibiotikum mit vielfältigen Anwendungsmöglichkeiten in der Gastroenterologie.

Rifaximin, a non-resorbable broadband antibiotic, was approved in Germany 2 years ago for the treatment of traveller's diarrhoea caused by non-invasive enteropathogens. On account of the very good tolerance and the high efficacy against almost all enteropathogens this pharmaceutical, which has been available for 25 years, bears a high potential in many other indications which are currently under clinical investigations, including: symptomatic uncomplicated diverticular disease, Clostridium difficile-associated diarrhoea and pseudomembranous colitis, small bowel intestinal bacterial overgrowth, irritable bowel syndrome and hepathic encephalopathy. The present overview demonstrates potential indications in the field of gastroenterology and critically reviews the significance of rifiximin in the treatment of these diseases based on the latest clinica data.

Functionalized silicon quantum dots tailored for targeted siRNA delivery.

For RNA interference (RNAi) mediated silencing of the ABCB1 gene in Caco-2 cells biocompatible luminescent silicon quantum dots (SiQDs) were developed to serve as self-tracking transfection tool for ABCB1 siRNA. While the 2-3nm sized SiQD core exhibits green luminescence, the QD surfaces are completely saturated with covalently linked 2-vinylpyridine that may electrostatically bind siRNA. For down-regulating P-glycoprotein (Pgp) expression of the ABCB1 gene the SiQDs were complexed with siRNA. The cellular uptake and allocation of SiQD-siRNA complexes in Caco-2 cells were monitored using confocal laser scanning microscopy and transmission electron microscopy. The release of siRNA to the cytoplasm was verified through real-time PCR quantification of the reduced ABCB1 mRNA level. Additional evidence was obtained from time-resolved in situ fluorescence spectroscopic monitoring of the Pgp efflux dynamics in transfected Caco-2 cells which yielded significantly reduced transporter efficiencies for the Pgp substrate Rhodamine 123.

Interaction of beta-blockers with the renal uptake transporter OCT2.

AIM: The uptake of drugs from the blood into the renal tubular cells is a key determinant for renal secretion and may influence their systemic plasma concentrations and extrarenal effects. Metformin, used for treatment of type 2 diabetes, is taken up into renal tubular cells by the organic cation transporter 2 (OCT2). Because many patients with type 2 diabetes receiving metformin are concomitantly treated with beta-blockers, we tested whether beta-blockers can inhibit OCT2-mediated drug transport. METHOD: Using Madin-Darby canine kidney II cells stably expressing the uptake transporter OCT2, we analysed whether the beta-blockers bisoprolol, carvedilol, metoprolol and propranolol inhibit the transport of OCT2 substrates 1-methyl-4-phenylpyridinium (MPP(+)) and metformin. RESULTS: Neither bisoprolol nor metoprolol significantly inhibited the uptake of MPP(+), whereas a significant inhibition was observed for carvedilol und propranolol (half maximal inhibitory concentration IC(50): 26.3 and 67.5 microM) respectively. Moreover, all beta-blockers significantly inhibited OCT2-mediated metformin uptake (IC(50) for bisoprolol: 2.4 microM, IC(50) for carvedilol: 2.3 microM, IC(50) for metoprolol: 50.2 microM and IC(50) for propranolol: 8.3 microM). CONCLUSION: These in vitro results demonstrate that alterations of uptake transporter function by beta-blockers have to be considered as potential mechanisms underlying drug-drug interactions in the kidney.

Contribution of multidrug and toxin extrusion protein 1 (MATE1) to renal secretion of trimethylamine-N-oxide (TMAO).

Trimethylamine-N-oxide (TMAO) gained considerable attention because of its role as a cardiovascular risk biomarker. Organic cation transporter 2 (OCT2) mediates TMAO uptake into renal proximal tubular cells. Here we investigated the potential role of multidrug and toxin extrusion protein 1 (MATE1) for translocation of TMAO across the luminal membrane of proximal tubular cells. HEK293 cells stably expressing OCT2 (HEK-OCT2) or MATE1 (HEK-MATE1) were used for uptake studies. Transcellular transport of TMAO was investigated using monolayers of MDCK control cells (MDCK-Co) as well as single- (MDCK-OCT2, MDCK-MATE1) and double-transfected cells (MDCK-OCT2-MATE1). In line with previous studies, HEK-OCT2 cells revealed a 2.4-fold uptake of TMAO compared to control cells (p < 0.001), whereas no significant uptake was observed in HEK-MATE1. In monolayers of MDCK cells, polarised TMAO transcellular transport was not significantly different between MDCK-Co and MDCK-OCT2 cells, but significantly increased in MDCK-MATE1 (p < 0.05) and MDCK-OCT2-MATE1 cells (p < 0.001). The OCT/MATE inhibitor trimethoprim abolished TMAO translocation in MDCK-OCT2-MATE1 cells (p < 0.05). The present data suggest that MATE1 contributes to renal elimination of TMAO. For selected MATE substrates, such as TMAO, uptake studies using non-polarised MATE-expressing cells can reveal false negative results compared to studies using polarised monolayers.

The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.

Currently available HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution, both of which are largely unexplained, complicate their use. We tested the hypothesis that P-glycoprotein is an important transporter for these agents. We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene. All three compounds were found to be transported by P-glycoprotein in vitro. After oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous administration, brain concentrations were elevated 7-36-fold. These data demonstrate that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. This raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity.

Valdecoxib does not interfere with the CYP2D6 substrate metoprolol.

OBJECTIVE: We reported recently that celecoxib inhibits the metabolism of the cytochrome P450 (CYP)2D6 substrate metoprolol in volunteers. Valdecoxib, the active metabolite of parecoxib, has also been claimed to interfere with the metabolism of CYP2D6 substrates. However, little support for this contention is available despite the intensive use of parecoxib in the perioperative setting. Therefore, the objective of this study was to examine the effect of valdecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. METHODS: An open, randomized, 3-period crossover study was performed in 15 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without, or following a 7-day pre-treatment with valdecoxib (20 mg, o.d.) or rofecoxib (25 mg, o.d.), to achieve steady state conditions of COX-2 inhibitors in Periods 2 and 3. In a small group of extensive metabolizers (EM/EM), short-term application of twice the dose was investigated. RESULTS: No effect of valdecoxib (20 mg/d) or rofecoxib (25 mg/d) were detected on the area under the plasma concentration-time curve of metoprolol (323 +/- 333 to 324 +/- 296 or 309 +/- 256 microg x h/l) or at a higher dose. No significant changes of pharmacokinetic or pharmacodynamic parameters of metoprolol were apparent. CONCLUSION: We conclude that, at therapeutic doses, valdecoxib and rofecoxib do not influence the CYP2D6 substrate metoprolol.

Human MRP3 transporter: identification of the 5'-flanking region, genomic organization and alternative splice variants.

In humans, at least six members of the multidrug resistance-associated protein (MRP) family are thought to exist. Here we report the molecular cloning of two splice variants of MRP3 from human liver. In addition, MRP3 genomic organization including the 5'-flanking region and a major portion of the MRP3 intron-exon organization are identified and characterized.

Consequences of rifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2D6.

Propafenone undergoes extensive metabolism both by phase I and phase II enzymes: cytochrome P4502D6 (CYP2D6) dependent polymorphic hydroxylation to its main metabolite 5-OH-propafenone, CYP3A4/1A2 dependent N-dealkylation and further glucuronidation and sulfation. Since CYP2D6 is not inducible by rifampicin, an important drug interaction between rifampicin and propafenone is not to be expected a priori. However, non-CYP2D6-dependent pathways may be induced as a case report described dramatically lowered plasma concentrations of propafenone with loss of dysrhythmia control associated with rifampicin treatment. Therefore, this study aimed to investigate induction properties of rifampicin on propafenone disposition in extensive metabolizers and poor metabolizers of CYP2D6. Six extensive metabolizers and six poor metabolizers ingested 600 mg rifampicin once daily for nine consecutive days. The day before the first rifampicin dose and on the day of the last rifampicin dose each individual received a single intravenous (i.v.) infusion of 140 mg unlabelled propafenone and 2 h later a single dose of 300 mg deuterated propafenone orally (p.o.). During enzyme induction maximum QRS prolongation decreased significantly after propafenone p.o. (21 +/- 7% versus 13 +/- 6% in extensive metabolizers, P < 0.01; 15 +/- 6% versus 9 +/- 6% in poor metabolizers, P < 0.01) and not after propafenone i.v. In parallel, there were no substantial differences in pharmacokinetics of propafenone i.v. by rifampicin. However, bioavailability of propafenone dropped from 30 +/- 15% to 10 +/- 8% in extensive metabolizers (P < 0.01) and from 81 +/- 6% to 48 +/- 8% in poor metabolizers (P < 0.001). Following propafenone p.o. clearances through N-dealkylation (4.1 +/- 2.1 ml/min versus 23.5 +/- 12.6 ml/min in extensive metabolizers, P < 0.01; 3.4 +/- 1.3 ml/min versus 16.0 +/- 5.5 ml/min in poor metabolizers, P < 0.001) and glucuronidation (123 +/- 48 ml/min versus 457 +/- 267 ml/min in extensive metabolizers, P < 0.05; 43 +/- 9 ml/min versus 112 +/- 34 ml/min in poor metabolizers, P < 0.01), but not 5-hydroxylation increased regardless of phenotype indicating substantial enzyme induction. Clearances to propafenone sulfate and conjugates of 5-OH-propafenone were significantly enhanced by rifampicin treatment in poor metabolizers (P < 0.01). Thus, induction of both phase I pathways (CYP3A4/1A2) and phase II pathways (glucuronidation, sulfation) of propafenone by rifampicin resulted in a clinically relevant metabolic drug interaction which was more pronounced in extensive metabolizers than in poor metabolizers with regard to percentage decrease in bioavailability of propafenone.

The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells.

P-glycoprotein (PGP) is a membrane protein which determines drug disposition in humans (e.g. digoxin). It is also expressed in various leukocyte lineages with highest expression in CD56+ natural killer cells. Recently, a polymorphism in exon 26 (C3435T) of this gene was shown to correlate with intestinal PGP expression and function in humans. Carriers homozygous for this polymorphism (TT) showed more than two-fold lower PGP expression and higher digoxin plasma concentrations compared to the CC group. However, it is not known whether this mutation in the MDR1 gene is also associated with altered PGP function in peripheral blood cells. We therefore assessed efflux of the PGP-substrate rhodamine 123 from CD56+ natural killer cells. Leukocytes were isolated from whole blood of 10 CC, 10 CT and 11 TT healthy Caucasian individuals. Using flow cytometry, rhodamine fluorescence was determined in CD56+ cells. Moreover, MDRI mRNA was quantified in leukocytes by real-time polymerase chain reaction. Subjects with CC genotype revealed a significantly lower rhodamine fluorescence (i.e. higher PGP function) compared to individuals with TT genotype (51.1 +/- 11.4% versus 67.5 +/- 9.5%, p < 0.01). Heterozygous individuals had an intermediate rhodamine fluorescence (61.4 +/- 6.3%). MDR1 mRNA normalized for cyclophilin was lowest in the TT population (1.29 +/- 1.01), intermediate in heterozygous subjects (1.60 +/- 0.76) and highest in the CC group (1.91 +/- 0.94; not significant). In summary, subjects being homozygous for C in position 3435 of the MDR1 gene have a more pronounced efflux of rhodamine from CD56+ natural killer cells and a higher MDR1 mRNA expression in leukocytes than subjects with the TT genotype. Measurement of rhodamine efflux using flow-cytometry from peripheral blood cells allows assessment of genetically determined differences in P-glycoprotein function.

Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans.

BACKGROUND: The opioid dihydrocodeine (DHC) is frequently used as an analgesic and antitussive agent. However, until now there have been no detailed data on dihydrocodeine metabolism in humans. We therefore investigated pathways that contribute to elimination of dihydrocodeine, and we tested the hypothesis that dihydrocodeine O-demethylation to dihydromorphine (DHM) is catalyzed by the polymorphic CYP2D6. METHODS: A single oral dose of dihydrocodeine was administered to six extensive (metabolic ratio [MR] < or = 1), two intermediate (1 < MR < 20) and six poor metabolizers (MR > or = 20) of sparteine/debrisoquin. Serum concentrations of dihydrocodeine and dihydromorphine were measured up to 25 hours, and urinary excretion of conjugated and unconjugated dihydrocodeine, dihydromorphine, and nordihydrocodeine were determined. RESULTS: There were no differences in the pharmacokinetics of dihydrocodeine between extensive and poor metabolizers. However, the area under the serum concentration-time curve (AUC), partial metabolic clearance, and total urinary recovery of dihydromorphine were significantly lower in poor metabolizers (10.3 +/- 6.1 nmol.hr/L; 7.0 +/- 4.1 ml/min; 1.3% +/- 0.9% of dose) compared with extensive metabolizers (75.5 +/- 42.9 nmol.hr/L; 49.7 +/- 29.9 ml/min; 8.9% +/- 6.2%; p < 0.01). There was a strong correlation between the AUCDHC/AUCDHM ratio and the urinary metabolic ratio of sparteine (rS = 0.89, p = 0.001). No significant differences between extensive and poor metabolizers were detected in urine for conjugated dihydrocodeine (extensive metabolizers, 27.7% of dose; poor metabolizers, 31.5%), unconjugated dihydrocodeine (extensive metabolizers, 31.1%; poor metabolizers, 31.1%), conjugated nordihydrocodeine (extensive metabolizers, 6.3%; poor metabolizers, 5.4%), or unconjugated nordihydrocodeine (extensive metabolizers, 15.8%; poor metabolizers, 19.5%). CONCLUSIONS: Dihydrocodeine O-demethylation to dihydromorphine is impaired in poor metabolizers of sparteine. The main urinary metabolites after administration of dihydrocodeine are the parent compound and its conjugates in extensive and poor metabolizers.

Disposition and pharmacologic effects of R/S-verapamil in patients with chronic atrial fibrillation: an investigation comparing single and multiple dosing.

BACKGROUND: Racemic (R /S)- verapamil is widely used in the management of chronic atrial fibrillation. The negative dromotropic effect is mainly mediated by the S -enantiomer, which is preferentially metabolized. Previous studies report an accumulation of R /S- verapamil during long-term oral treatment of patients with chronic atrial fibrillation. However, the specific disposition of S -verapamil and the pharmacologic effects were not assessed. Therefore uncertainties about the need for dose adjustments remain. METHODS: Using stable isotope technology and a stereospecific assay, we compared the pharmacokinetics and pharmacodynamics of intravenous (10 mg of d(7)-R /S -verapamil) and oral (240 mg of slow release (SR) d(0)-R /S -verapamil) R -verapamil and S -verapamil after the first dose (day 1) and after 3 weeks (day 21) of continuous oral therapy in 8 patients with long-term atrial fibrillation. On both study days, serum samples were obtained for the analysis of d(7)- and d(0)-R -verapamil and S -verapamil. Heart rate (HR) was monitored with electrocardiography (with each blood sample) and Holter electrocardiography (before the study, on day 1, and on day 21). RESULTS: Compared with day 1, clearance of oral R -verapamil and S -verapamil was significantly reduced on day 21 (1007 +/- 380 versus 651 +/- 253 mL/min [-35%] and 5481 +/- 2731 versus 2855 +/- 1097 mL/min [-48%], respectively; P <.05), whereas only a moderate decrease was observed for intravenous R -verapamil and S -verapamil (-23% and -14%, respectively, not significant). Mean HR (89 +/- 11 bpm before verapamil) was effectively reduced, with the same effects on day 1 (68 +/- 8 bpm) and day 21 (68 +/- 8 bpm). Compared with day 1, the HR reduction per ng/mL of S -verapamil (calculated by the area under the curve [from 0-24 hours] ratio of HR reduction and S -verapamil concentration) was significantly lower on day 21 (0.7 +/- 0.4 versus 1.2 +/- 0.7 [bpm]. [ng/mL](-1), for day 21 versus day 1; P <.01). CONCLUSIONS: In patients with chronic atrial fibrillation, clearance of oral, but not intravenous, S -verapamil and R -verapamil is significantly reduced with multiple doses compared with a single dose, thereby indicating predominant impairment of prehepatic rather than hepatic metabolism as the underlying mechanism. However, this kinetic change is clinically compensated by a decrease in the responsiveness to S -verapamil observed with regular dosing. The data suggest that despite accumulation of the drug individual verapamil doses can be maintained during long-term oral rate control therapy.

Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique.

BACKGROUND AND AIMS: The contribution of the gastrointestinal tract in comparison with the liver for the low and variable bioavailability of orally administered drugs is still poorly understood. Here we report on a new intestinal perfusion technique for the direct assessment of absorption, metabolism, and transport of drugs by the intestinal wall. METHODS: In 6 healthy volunteers a multilumen perfusion catheter was used to generate a 20-cm isolated jejunal segment that was perfused with 80 mg verapamil. Simultaneously, 5 mg [(2)H(7)]verapamil was given intravenously. Blood, perfusate, and bile samples were analyzed for parent verapamil and its major metabolites. RESULTS: The mean fraction of the verapamil dose absorbed from the 20-cm segment was 0.76 but substantial interindividual variability (0.51-0.96) was shown. Bioavailability was low (19.3%). The intestinal wall contributed to the same extent as the liver to extensive first-pass metabolism (mean extraction ratio, 0.49 versus 0.48). Substantial transport of verapamil metabolites from the systemic circulation via the enterocytes into the intestinal lumen was observed. Compared with biliary excretion, intestinal secretion into a 20-cm jejunal segment contributed to drug elimination to a similar extent. CONCLUSION: First-pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites.

Loss of analgesic effect of morphine due to coadministration of rifampin.

Methadone withdrawal symptoms have been reported in drug addicts treated with the tuberculostatic rifampin. Whereas this interaction can be explained by induction of phase I drug metabolism (CYP3A4), knowledge about induction of phase II metabolism (e.g., UDP-glucuronosyltransferases = UGTs) and its influence on drug effects in man, however, is very limited. The potent analgesic morphine is metabolized by more than one UGT to the active metabolite morphine-6-glucuronide and to morphine-3-glucuronide, which is devoid of analgesic activity. Thus, differential induction of UGTs involved in metabolism of morphine might lead to decreased or increased analgesic effects, depending on which UGT is preferentially induced. We therefore investigated the influence of the potent enzyme inducer rifampin on analgesic effects and pharmacokinetics of morphine, which is primarily eliminated by phase II metabolism. Ten healthy male volunteers participated in this double-blind, placebo-controlled study with double crossover design. Morphine (10 mg p.o.) and placebo were administered on two separate occasions before and near the end of 13 days of treatment with rifampin (600 mg/day). Blood samples were collected for 31 h. Morphine effects on pain sensation were determined using the cold pressor test. When morphine was given alone, the opioid elicited a significant increase in pain threshold and pain tolerance in comparison to placebo (P < or = 0.05). However, following administration of rifampin no analgesic effect of morphine was observed. In agreement, the area under the serum concentration-time curve (AUC) of morphine and the maximum serum concentration of morphine were considerably reduced during coadministration of rifampin (-27.7 +/- 19.3% and -40.7 +/- 27.1%; P < or = 0.01). Moreover, during treatment with rifampin a proportional reduction of AUCs of morphine-3-glucuronide (P < or = 0.01), morphine-6-glucuronide (P < or = 0.05) and morphine was observed. Since urinary recoveries of both morphine-3-glucuronide and morphine-6-glucuronide were also reduced during administration of rifampin, there is no evidence for a contribution of UGT induction to the observed interaction. In summary, a major drug interaction was observed between morphine and rifampin, which could not be attributed to induction of UGTs, but resulted in a complete loss of analgesic effects of the opioid.

Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein.

Proton pump inhibitors are a class of drugs which are widely prescribed for acid-related diseases. They are primarily metabolized by CYP2C19 and CYP3A4. It is unknown so far whether proton pump inhibitors are also substrates of the ATP-dependent efflux transporter P-glycoprotein. Moreover, it is not established whether proton pump inhibitors are also inhibitors of P-glycoprotein function. The aim of our study was therefore to characterize omeprazole, lansoprazole and pantoprazole as P-glycoprotein substrates and inhibitors. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells. Inhibition of P-glycoprotein-mediated transport was determined using the cyclosporine analogue PSC-833 (valspodar) as P-glycoprotein inhibitor. Inhibition of efflux transport by omeprazole, lansoprazole and pantoprazole was assessed using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, basal-to-apical transport of omeprazole, lansoprazole and pantoprazole was greater than apical-to-basal transport in Caco-2 and L-MDRI cells. Addition of PSC-833 (1 microM) showed a clear effect only for lansoprazole, suggesting that other transporters contribute to omeprazole and pantoprazole cellular translocation. Furthermore, all of the tested compounds inhibited digoxin transport with IC50 values of 17.7, 17.9 and 62.8 microM for omeprazole, pantoprazole and lansoprazole, respectively. In summary, our data provide evidence that proton pump inhibitors are substrates and inhibitors of P-glycoprotein. These findings might explain some of the drug interactions with proton pump inhibitors observed in vivo.

P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin.

Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs.

Transport by ATP-dependent efflux pumps such as P-glycoprotein is an increasingly recognized determinant of drug disposition. P-glycoprotein does not only contribute to multidrug resistance (MDR) in tumor cells, it is also expressed in normal tissues with excretory function such as liver, kidney and intestine. Apical expression of P-glycoprotein in such tissues results in reduced drug absorption from the gastrointestinal tract and enhanced drug elimination into bile and urine. Moreover, expression of P-glycoprotein in the endothelial cells of the blood-brain barrier prevents entry of certain drugs into the central nervous system. Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, cyclosporine and HIV-1 protease inhibitors. Drug administration to P-glycoprotein knock-out and control mice provided data on the importance of P-glycoprotein for absorption after oral administration and penetration through the blood-brain barrier. Moreover, P-glycoprotein knock-out mice were used to identify inhibition of P-glycoprotein-mediated transport as a mechanism for drug interactions such as the digoxin-quinidine interaction. Studies in humans indicate a particular importance of intestinal P-glycoprotein for bioavailability of the immunosuppressant cyclosporine. Moreover, induction of intestinal P-glycoprotein by rifampin has now been identified as the major underlying mechanism of reduced digoxin plasma concentrations during concomitant rifampin therapy. In summary, P-glycoprotein functions as a defense mechanism, which determines bioavailability and CNS concentrations of drugs. Modification of P-glycoprotein function is an important underlying mechanism of drug interactions in humans. However, disposition of a drug and its metabolites frequently is not only determined by P-glycoprotein, but also by drug-metabolizing enzymes and possibly by drug transporters other than P-glycoprotein [e.g. members of the MRP family (MRP = multidrug resistance-associated proteins)].

Inconsistencies and misleading information in officially approved prescribing information from three major drug markets.

The summary of product characteristics (SPC) should provide information for the safe prescription and use of a drug. We evaluated the consistency of critical interaction warnings, the quality of presentation of undesirable effects as well as concordance of critical information of representative drugs marketed in the United States, the UK, and Germany. Reciprocal warnings regarding drug-drug interactions that constitute contraindications were frequently missing in the SPCs of the drugs concerned (all countries >40%). Most SPCs did not explicitly exclude adverse reactions considered not reasonably attributable to the use of the drug. Comparing SPCs of different generic brands of the same drug, only 60, 10, and 20% of the US, UK, and German SPCs, respectively, provided identical contraindications. Current SPCs contain inconsistencies and misleading data that are not compatible with the purpose of SPCs, which is to provide a basis for the safe prescription and use of drugs.

Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the ß-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-48)) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [(3)H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion-transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (K(m)) = 84.3 µmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC(50) = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine.

Prediction of transporter-mediated drug-drug interactions using endogenous compounds.

Therapy with two or more drugs is more the rule than the exception, particularly in aging societies. Drug-drug interactions are frequently undesirable and may lead to increased toxicity and mortality. Inhibition of transporters is one major mechanism underlying drug-drug interactions. The myriad of potential drug combinations makes it very challenging to predict drug-drug interactions. This Commentary discusses potential advantages and limitations of endogenous compounds for predicting transporter-mediated drug-drug interactions.

Interaction of innovative small molecule drugs used for cancer therapy with drug transporters.

Multiple new small molecules such as tyrosine kinase, mammalian target of rapamycin (mTOR) and proteasome inhibitors have been approved in the last decade and are a considerable progress for cancer therapy. Drug transporters are important determinants of drug concentrations in the systemic circulation. Moreover, expression of drug transporters in blood-tissue barriers (e.g. blood-brain barrier) can limit access of small molecules to the tumour (e.g. brain tumour). Finally, transporter expression and (up)regulation in the tumour itself is known to affect local drug concentrations in the tumour tissue contributing to multidrug resistance observed for multiple anticancer agents. This review summarizes the current knowledge on: (i) small molecules as substrates of uptake and efflux transporters; (ii) the impact of transporter deficiency in knockout mouse models on plasma and tissue concentrations; (iii) small molecules as inhibitors of uptake and efflux transporters with possible consequences for drug-drug interactions and the reversal of multidrug resistance; and (iv) on clinical studies investigating the association of polymorphisms in genes encoding drug transporters with pharmacokinetics, outcome and toxicity during treatment with the small molecules.