Karin Dilger

Publications of Karin Dilger

• Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health.

  Authors: Karin Dilger, Simon Hohenester, Ursula Winkler-Budenhofer, Barbara A J Bastiaansen, Frank G Schaap, Christian Rust, Ulrich Beuers

  Journal of hepatology. 03/2012;

  BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. ItsBACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. Its adequate biliary enrichment is considered mandatory for therapeutic efficacy. However, precise determination of biliary enrichment of UDCA is not possible in clinical practice. Therefore, we investigated (i) the relationship between biliary enrichment and plasma pharmacokinetics of UDCA, (ii) the effect of UDCA on plasma and biliary bile acid composition and conjugation patterns, and (iii) on the intestinal detoxification machinery in patients with PBC and healthy controls. METHODS: In eleven PBC patients and eleven matched healthy subjects, cystic bile and duodenal tissue were collected before and after three weeks of administration of UDCA (15 mg/kg/day). Extensive pharmacokinetic profiling of bile acids was performed. The effect of UDCA on the intestinal detoxification machinery was studied by quantitative PCR and Western blotting. RESULTS: The relative fraction of UDCA and its conjugates in plasma at trough level[x] correlated with their biliary enrichment[y] (r=0.73,p=0.0001,y=3.65+0.49(∗)x). Taurine conjugates of the major hydrophobic bile acid, chenodeoxycholic acid, were more prominent in bile of PBC patients than in that of healthy controls. Biliary bile acid conjugation patterns normalized after treatment with UDCA. UDCA induced duodenal expression of key export pumps, BCRP and P-glycoprotein. CONCLUSIONS: Biliary and trough plasma enrichment of UDCA are closely correlated in PBC and health. Taurine conjugation may represent an adaptive mechanism in PBC against chenodeoxycholic acid-mediated bile duct damage. UDCA may stabilize small intestinal detoxification by up-regulation of efflux pumps.

• Characterization of Ursodeoxycholic and Norursodeoxycholic Acid as Substrates of the Hepatic Uptake Transporters OATP1B1, OATP1B3, OATP2B1 and NTCP.

  Authors: Jörg König, Sabine Klatt, Karin Dilger, Martin F Fromm

  Basic & clinical pharmacology & toxicology. 02/2012;

  Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) is currently tested in clinical trials for future treatment of primaryUrsodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) is currently tested in clinical trials for future treatment of primary sclerosing cholangitis because of beneficial effects in cholestatic Mdr2 knock-out mice. Uptake of UDCA and norUDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and norUDCA are poorly understood. We therefore investigated whether UDCA and norUDCA are substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and Na(+) -taurocholate co-transporting polypeptide (NTCP), which are localized in the basolateral membrane of hepatocytes. Uptake of [(3) H]UDCA and [(14) C]norUDCA into Human embryonic kidney (HEK) cells stably expressing OATP1B1, OATP1B3, OATP2B1 or NTCP was investigated and compared with uptake into vector control cells. Uptake ratios were calculated by dividing uptake into transporter-transfected cells by uptake into respective control cells. Uptake ratios of OATP1B1-, OATP1B3- and OATP2B1-mediated UDCA and norUDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was significantly higher into HEK-NTCP cells only at the lowest tested concentration (1 μM, p < 0.001) compared with the control cells with an uptake ratio of 1.34-fold. NorUDCA was not significantly transported by NTCP. The low uptake rates suggest that OATP1B1, OATP1B3, OATP2B1 and NTCP are not relevant for hepatocellular uptake and effects of UDCA and norUDCA in human beings.

• 3g mesalazine granules are superior to 9mg budesonide for achieving remission in active ulcerative colitis: a double-blind, double-dummy, randomised trial.

  Authors: Volker Gross, Ivan Bunganic, Elena A Belousova, Tatyana L Mikhailova, Limas Kupcinskas, Gediminas Kiudelis, Zsolt Tulassay, Libor Gabalec, Andrey E Dorofeyev, Jelena Derova, Karin Dilger, Roland Greinwald, Ralph Mueller

  Journal of Crohn's & colitis. 04/2011; 5(2):129-38.

  Budesonide may be an effective therapy for mild-to-moderately active ulcerative colitis (UC). This study aimed to demonstrate non-inferiority for oral 9mg budesonide once daily (OD) versus 3gBudesonide may be an effective therapy for mild-to-moderately active ulcerative colitis (UC). This study aimed to demonstrate non-inferiority for oral 9mg budesonide once daily (OD) versus 3g mesalazine granules OD. This was an eight-week randomised, double-blind, double-dummy, multicentre study in which patients with mild-to-moderately active UC, defined as Clinical Activity Index (CAI) ≥6 and Endoscopic Index (EI) ≥4, received budesonide (Budenofalk® 3mg capsules×3) or mesalazine (Salofalk® 1000mg granules×3). The primary endpoint was clinical remission at week 8 (CAI ≤4 with stool frequency and rectal bleeding subscores of "0"). 343 patients were randomised (177 budesonide, 166 mesalazine). Fewer patients achieved the primary endpoint with budesonide versus mesalazine (70/177 [39.5%] versus 91/166 [54.8%]) with a difference in proportions of -15.3% (95% CI [-25.7%, -4.8%]; p=0.520 for non-inferiority). The median time to first resolution of symptoms was 14.0 days (budesonide) and 11.0 days (mesalazine) (hazard ratio 1.19; 95% CI [0.94, 1.51]). Mucosal healing was observed in 54/177 (30.5%) budesonide patients versus 65/166 (39.2%) mesalazine patients, a difference of -8.6% (95% CI [-18.7%, 1.4%]; p=0.093). The incidences of adverse events (budesonide 26.6%, mesalazine 25.3%) and serious adverse events (budesonide 1.7%, mesalazine 1.2%) were similar. Once-daily 3g mesalazine administered as granules is superior to 9mg budesonide OD administered as capsules for achieving remission in mild-to-moderately active UC. However, it is noteworthy that remission of UC was attained in about 40% of budesonide-treated patients with a rapid onset of resolution.

• Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn's disease.

  Authors: Andreas Tromm, Ivan Bunganič, Eva Tomsová, Zsolt Tulassay, Milan Lukáš, Jan Kykal, Marian Bátovský, Bohumil Fixa, Libor Gabalec, Rifaat Safadi [......] István Altorjay, Hanns Löhr, Ioannis Koutroubakis, Simon Bar-Meir, Davor Stimac, Elke Schäffeler, Christoph Glasmacher, Karin Dilger, Ralf Mohrbacher, Roland Greinwald

  Gastroenterology. 11/2010; 140(2):425-434.e1; quiz e13-4.

  Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients withComparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD. We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L-coated oral mesalamine (4.5 g/day). The primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, -4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups. Budesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-L-coated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen.

• Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial.

  Authors: Walter Reinisch, Sieglinde Angelberger, Wolfgang Petritsch, Olga Shonova, Milan Lukas, Simon Bar-Meir, Alexander Teml, Elke Schaeffeler, Matthias Schwab, Karin Dilger, Roland Greinwald, Ralph Mueller, Eduard F Stange, Klaus R Herrlinger

  Gut. 06/2010; 59(6):752-9.

  The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severeThe aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severe endoscopic recurrence. This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6-24 months without subsequent clinical recurrence and with a Crohn's disease activity index (CDAI) score <200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0-2.5 mg/kg/day or mesalazine 4 g/day over 1 year. The primary end point was therapeutic failure during 1 year, defined as a CDAI score > or = 200 and an increase of > or = 60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction. Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI -5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showing > or = 1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023). In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure.

• Clinical trial: a novel high-dose 1 g mesalamine suppository (Salofalk) once daily is as efficacious as a 500-mg suppository thrice daily in active ulcerative proctitis.

  Authors: Tilo Andus, Andreas Kocjan, Moritz Müser, Andrey Baranovsky, Tatyana L Mikhailova, Tatyana D Zvyagintseva, Andrey E Dorofeyev, Yurii S Lozynskyy, Ingolf Cascorbi, Manfred Stolte, Michael Vieth, Karin Dilger, Ralf Mohrbacher, Roland Greinwald

  Inflammatory bowel diseases. 03/2010; 16(11):1947-56.

  Mesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show theMesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show the noninferiority of once-daily administration of a novel 1 g mesalamine suppository versus thrice-daily administration of the 0.5 g mesalamine suppository. This was a single-blind (investigator-blinded), randomized, multicenter, comparative, Phase III clinical trial. Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6-week period. The primary endpoint was rate of remission (Disease Activity Index below 4). In all, 354 patients were evaluable for safety and per-protocol analysis. The new regimen demonstrated noninferiority: The percentage of patients with remission was 87.9% for the once-daily 1 g mesalamine suppository and 90.7% for the thrice-daily 0.5 g mesalamine suppository. Each regimen resulted in prompt cessation of clinical symptoms (e.g., median time to ≤3 stools per day (all without blood): 5 days in the 1 g mesalamine once-daily and 7 days in the 0.5 g mesalamine thrice-daily group). Patients preferred applying suppositories once a day. In active ulcerative proctitis the once-daily administration of a 1 g mesalamine suppository is as effective and safe, yet considerably more convenient, than the standard thrice-daily administration of a 0.5 g mesalamine suppository.

• Pharmacokinetics and Pharmacodynamic Action of Budesonide after Buccal Administration in Healthy Subjects and Patients with Oral Chronic Graft-versus-Host Disease.

  Authors: Karin Dilger, Jörg Halter, Hartmut Bertz, Luis Lopez-Lazaro, Alois Gratwohl, Jürgen Finke

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 04/2009; 15(3):336-343.

  Buccal administration of budesonide (mouthwash) may be effective as a topical add-on therapy in patients with oral chronic graft-versus-host disease (cGVHD). Safety of approved oral budesonide isBuccal administration of budesonide (mouthwash) may be effective as a topical add-on therapy in patients with oral chronic graft-versus-host disease (cGVHD). Safety of approved oral budesonide is based on high intestinal and hepatic extraction by cytochrome P450 3A (CYP3A) enzymes. The purpose of this study was to evaluate the presystemic extraction and pharmacodynamic action of buccal budesonide. Oral budesonide (3 mg) was taken as reference to which various single and multiple dose regimens of buccal budesonide were compared. Budesonide and the 2 main CYP3A-dependent metabolites (6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone) were analyzed in blood and urine along with the drug's effect on endogenous cortisol in 12 healthy subjects and 7 patients with oral cGVHD. We assessed CYP3A-dependent metabolites in both healthy subjects and patients after buccal budesonide. Whereas systemic exposure to budesonide was markedly lower in healthy subjects after the mouthwash compared to oral dosing (mean relative bioavailability 18%-36%), the systemic concentrations thereafter in patients were as high as those after the identical dose of oral budesonide. Reduced buccal CYP3A activity (lower inactivation of budesonide) in patients contributed to this remarkable difference. Endogenous cortisol was suppressed in some patients during 1 week of continuous treatment with buccal budesonide (3 x 3 mg per day). We are the first to report the biotransformation of budesonide via CYP3A enzymes after buccal drug administration. Only 2% of a buccal dose of budesonide achieves systemic circulation in healthy individuals; that fraction is 10% in patients with oral cGVHD, probably because of alterations in drug uptake and metabolization.

• Effect of high-dose metronidazole on pharmacokinetics of oral budesonide and vice versa: a double drug interaction study.

  Authors: Karin Dilger, Richard Fux, Daniel Röck, Klaus Mörike, Christoph H Gleiter

  Journal of clinical pharmacology. 01/2008; 47(12):1532-9.

  Recent case reports suggest that addition of high-dose metronidazole might be associated with elevated plasma concentrations of substrates of cytochrome P450 (CYP) 3A. Because patients withRecent case reports suggest that addition of high-dose metronidazole might be associated with elevated plasma concentrations of substrates of cytochrome P450 (CYP) 3A. Because patients with fistulizing Crohn's disease benefit by using high doses of metronidazole for prolonged periods, this study's primary aim was to evaluate the effect of high-dose metronidazole on the pharmacokinetics of oral budesonide, a sensitive substrate of CYP3A commonly prescribed in acute inflammatory bowel disease. Twelve healthy adults received 1.5 g metronidazole per day over 1 week. The CYP3A-dependent metabolic profile of an oral dose of budesonide (3 mg) and that of endogenous cortisol were compared intraindividually before and after administration of metronidazole. There was neither a significant effect of high-dose metronidazole on the area under the plasma concentration-time curve (AUC) of budesonide (90% confidence interval, 79%-115%) nor on the AUC ratios of 6beta-hydroxybudesonide/budesonide and 16alpha-hydroxyprednisolone/budesonide. In parallel, metronidazole did not significantly alter formation of 6beta-hydroxycortisol. Vice versa, budesonide did not affect the AUC of metronidazole (90% confidence interval, 91%-100%). The authors conclude that in contrast to concomitant intake of other imidazoles such as ketoconazole, concomitant intake of metronidazole may not lead to serious safety concerns due to elevated systemic concentrations of the glucocorticoid budesonide.

• Monitoring of thiopurine methyltransferase activity in postsurgical patients with Crohn's disease during 1 year of treatment with azathioprine or mesalazine.

  Authors: Karin Dilger, Elke Schaeffeler, Milan Lukas, Ulrike Strauch, Hans Herfarth, Ralph Müller, Matthias Schwab

  Therapeutic drug monitoring. 03/2007; 29(1):1-5.

  Thiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine orThiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolites was performed prospectively during a 1 year postoperative period in 21 patients with Crohn's disease randomly assigned to azathioprine (2.0-2.5 mg/kg per day) or mesalazine (4 g/day). TPMT activity did not change significantly within each treatment group during 52 weeks. At any study visit, TPMT activity was not different between 13 patients on azathioprine and eight patients on mesalazine. Concentrations of 6-thioguanine nucleotides (6-TGN, active moiety of azathioprine) and 6-methyl-mercaptopurine ribonucleotides (6-MMPR) did not alter significantly during the observation period, except for a slight decrease in 6-TGN levels when comparing the first with the last visit. In this first report of serial monitoring of 6-methyl-thioguanine nucleotides (6-MTGN) in patients with inflammatory bowel disease taking azathioprine, high levels of 6-TGN were correlated with high levels of 6-MTGN, with the mean 6-TGN:6-MTGN ratio being 2.4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor azathioprine significantly affected TPMT activity during a whole year of treatment.

• Multidrug resistance 1 genotype and disposition of budesonide in early primary biliary cirrhosis.

  Authors: Karin Dilger, Ingolf Cascorbi, Frank Grünhage, Simon Hohenester, Tilman Sauerbruch, Ulrich Beuers

  Liver international : official journal of the International Association for the Study of the Liver. 05/2006; 26(3):285-90.

  BACKGROUND: Budesonide, which is a dual substrate of P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, and cytochrome P450 3A (CYP3A) has been proposed for treatment of earlyBACKGROUND: Budesonide, which is a dual substrate of P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, and cytochrome P450 3A (CYP3A) has been proposed for treatment of early primary biliary cirrhosis (PBC). Recently, MDR1 gene polymorphisms have been discussed as a potential cause of glucocorticoid resistance. We tested the hypothesis that MDR1 gene polymorphisms affect absorption of oral budesonide. METHODS: In 21 patients with histologically proven early-stage (I/II) PBC and nine healthy subjects, we evaluated the impact of MDR1 single nucleotide polymorphisms (2,677G>T,A and 3,435C>T) on disposition of a single oral dose of 3 mg budesonide. CYP3A5 gene polymorphisms (6,986A>G) were analyzed in parallel. RESULTS: In MDR1 2,677 GG and 3,435 CC genotypes, absorption and elimination of budesonide were not significantly different from those in corresponding homozygous variants. Peak plasma levels and areas under the plasma concentration time curves (AUC) of budesonide were not lower in MDR1 3,435 CC with putatively high intestinal expression of P-glycoprotein than in MDR1 3,435 TT. Interestingly, in two CYP3A5*1/*3 carriers with high enzyme activity, lower AUC was noted than in 28 CYP3A5*3/*3 carriers with a deficient enzyme. CONCLUSION: Common MDR1 gene polymorphisms do not affect disposition of budesonide in early PBC.

• No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis.

  Authors: Karin Dilger, Annette Denk, Malte H J Heeg, Ulrich Beuers

  Hepatology (Baltimore, Md.). 04/2005; 41(3):595-602.

  Induction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis. CYP3A is of key importance in human drug metabolism, being involvedInduction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis. CYP3A is of key importance in human drug metabolism, being involved in presystemic extraction of more than 50% of all drugs currently available and of various endogenous compounds. Therefore, we compared the induction potential of UDCA with that of the prototypical inducer rifampicin in a human model study with the CYP3A substrates budesonide and cortisol. Twelve patients with early-stage primary biliary cirrhosis and eight healthy volunteers were treated with UDCA (15 mg/kg daily) for 3 weeks and subsequently with rifampicin (600 mg/d) for 1 week. Extensive pharmacokinetic profiling of oral budesonide (3 mg) was performed by determination of budesonide and phase I metabolites (6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone) in plasma and urine at baseline and at the end of each treatment. In parallel, urinary 6beta-hydroxycortisol, a validated marker of CYP3A induction, was determined. UDCA did not affect biotransformation of budesonide and urinary excretion of 6beta-hydroxycortisol either in patients or in healthy volunteers. Ratios of areas under plasma concentration-time curves (AUC(0-12 h) during UDCA/AUC(0-12 h) before UDCA) of both metabolites were not higher than those of budesonide itself. In contrast, administration of rifampicin markedly induced CYP3A metabolism, resulting in abolished budesonide plasma levels and high urinary excretion of 6beta-hydroxycortisol. Metabolite formation was enhanced by rifampicin, but not by UDCA (e.g., AUC(16alpha-hydroxyprednisolone)/AUC(budesonide) in patients: baseline, 8.6 +/- 3.9; UDCA, 10.7 +/- 7.1; rifampicin, 527.0 +/- 248.7). In conclusion, UDCA is not a relevant inducer of CYP3A enzymes in humans.

• Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein.

  Authors: Karin Dilger, Matthias Schwab, Martin F Fromm

  Inflammatory bowel diseases. 10/2004; 10(5):578-83.

  Steroid resistance is a major problem in the management of patients with inflammatory bowel disease. In Crohn disease, poor response to corticosteroids has been related to increased expression of theSteroid resistance is a major problem in the management of patients with inflammatory bowel disease. In Crohn disease, poor response to corticosteroids has been related to increased expression of the drug efflux pump, P-glycoprotein. However, it has not been investigated thoroughly whether corticosteroids commonly used for drug therapy in inflammatory bowel disease are substrates of P-glycoprotein. We tested the hypothesis that budesonide and prednisone are substrates of P-glycoprotein thereby possibly contributing to variable therapeutic effects. Polarized, basal to apical transport of [3H]budesonide and [3H]prednisone was studied in monolayers of L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1 cDNA) and Caco-2 cells, both of which express P-glycoprotein in their apical membrane. Drug transport was measured during 4 hours at substrate concentrations of 5 microM. Net transport rates and permeability coefficients were calculated. Inhibition of P-glycoprotein-mediated transport across Caco-2 monolayers was determined after addition of the P-glycoprotein inhibitor PSC-833. The net transport rate from the basolateral to the apical side was significantly higher in L-MDR1 than in LLC-PK1 cells for both budesonide and prednisone. Apparent permeability coefficients of budesonide and prednisone reflected polarized transport from basal to apical. PSC-833 inhibited the polarized transport of both corticosteroids. In conclusion, budesonide and prednisone were identified as substrates of the intestinal drug efflux pump, P-glycoprotein. Therefore, drug secretion via P-glyco-protein into gut lumen might play a more important role in pharmacokinetics and pharmacodynamics of these corticosteroids than currently appreciated in gastroenterological practice.

• Pharmacokinetics of mesalazine pellets in children with inflammatory bowel disease.

  Authors: Heleen Wiersma, Johanna C Escher, Karin Dilger, Dietmar Trenk, Marc A Benninga, Chris J van Boxtel, Jan Taminiau

  Inflammatory bowel diseases. 10/2004; 10(5):626-31.

  Mesalazine is a first-line drug in pediatric inflammatory bowel disease (IBD), and is customarily used to induce and maintain remission in mild to moderate disease. In children, pharmacokinetic dataMesalazine is a first-line drug in pediatric inflammatory bowel disease (IBD), and is customarily used to induce and maintain remission in mild to moderate disease. In children, pharmacokinetic data are scarce, and dosage recommendations are largely extrapolated from studies in adults. Aim of the study was to obtain the pharmacokinetic profile of a new mesalazine pellet formulation in children with ulcerative colitis and Crohn's colitis. A single oral dose of 20 mg/kg mesalazine was administered to 13 patients (age 6-16 years). Serial blood and urine sampling for determination of mesalazine and acetylmesalazine was performed before and during 24 hours following ingestion. Maximum plasma concentration of mesalazine (Cmax) was 1332 ng/mL (geometric mean, geometric coefficient of variation [CV]: 0.57), obtained 3.7 hours (tmax; CV: 0.31) after drug administration. Systemic exposure as determined by area under the plasma concentration-time curve (AUC(0-infinity) ) was 8712 ng/ml*h (CV: 0.44). Terminal half-life of elimination of mesalazine was 3.5 hours (t(1/2); CV: 1.43). This study presents extensive pharmacokinetic data on mesalazine in children with mild-moderately active ulcerative colitis and Crohn's colitis. In comparison with previous experience in adults, pharmacokinetics of mesalazine administered as pellets appear to be similar in both populations.

• Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis.

  Authors: Wolfgang Hempfling, Frank Grunhage, Karin Dilger, Christoph Reichel, Ulrich Beuers, Tilman Sauerbruch

  Hepatology (Baltimore, Md.). 08/2003; 38(1):196-202.

  Budesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBCBudesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBC stage I/II and stage IV. Twelve patients with early PBC stage I/II and 7 patients with PBC stage IV under continuous treatment with ursodeoxycholic acid (UDCA) were enrolled in an exploratory trial. Each patient received oral budesonide for 3 weeks at weekly increasing dosages of 3 mg once to thrice per day. Budesonide and cortisol plasma levels, urinary cortisol excretion, serum liver tests, and immunoglobulins were determined on days 1, 7, and 21 of the study. Patients with PBC stage IV showed significantly higher peak plasma concentrations (4.9 +/- 3.5 vs. 1.5 +/- 0.4 ng/mL; P <.05) and areas under the plasma concentration-time curves (AUC) (23.2 +/- 16.8 vs. 5.1 +/- 1.4 hours. ng/mL, P <.01, total AUC extrapolated to infinity [AUC(0- infinity )]) after a single dose of 3 mg budesonide when compared with patients with PBC stage I/II. Equally, AUC of budesonide were significantly increased under a multiple dose regimen on day 21 (14.0 +/- 11.6 vs. 5.0 +/- 1.9 hours. ng/mL, P <.01, AUC at steady state from dosing time to 8 hours [AUC(ss,0-8 h)]). Higher levels of budesonide were related to a significant decrease in plasma cortisol and reduction of urinary cortisol excretion in patients with stage IV disease. Two patients with stage IV disease developed portal vein thrombosis (PVT). In conclusion, administration of budesonide leads to markedly elevated plasma levels in cirrhotic patients with PBC associated with serious adverse drug reactions. Thus, further evaluation of combined treatment with UDCA may be considered in early-stage PBC but not in cirrhotic patients with PBC.

• Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib.

  Authors: Stefanie S Brenner, Charlotte Herrlinger, Karin Dilger, Thomas E Mürdter, Ute Hofmann, Claudia Marx, Ulrich Klotz

  Clinical pharmacokinetics. 01/2003; 42(3):283-92.

  OBJECTIVE: To analyse the influence of age and cytochrome P450 (CYP) 2C9 genotype on the steady-state disposition of the standard NSAID diclofenac and the new COX-2 selective inhibitor celecoxib,OBJECTIVE: To analyse the influence of age and cytochrome P450 (CYP) 2C9 genotype on the steady-state disposition of the standard NSAID diclofenac and the new COX-2 selective inhibitor celecoxib, both of which are metabolised by the polymorphically expressed CYP2C9. DESIGN: Double-blind randomised crossover study under steady-state conditions. SUBJECTS: 12 young (age 32 +/- 5 years, bodyweight 71 +/- 12kg; mean +/- SD) and 12 elderly (68 +/- 2 years, 82 +/- 15kg) healthy, drug-free, nonsmoking Caucasians of both sexes. METHODS: All subjects received oral celecoxib (200mg twice daily) and diclofenac (75mg twice daily) for 15 days separated by a drug-free interval of at least 3 weeks. Following the last morning dose, multiple blood samples were taken for 25 hours. Concentrations of celecoxib and diclofenac were measured by specific and sensitive high performance liquid chromatography. Identification of CYP2C9 genotype was performed by genomic DNA sequencing. Pharmacokinetic parameters for total and unbound drugs were individually analysed by noncompartmental techniques. RESULTS: For diclofenac, area under the concentration-time curve over the dosage interval (AUC(tau)) was larger in young subjects (3.2 +/- 1.0 mg * h/L) than in older individuals (2.4 +/- 0.4 mg * h/L; p < 0.05). As the terminal half-life (t((1/2)Z)) was very similar in both groups (3.9 +/- 4.4 vs 3.5 +/- 3.3 hours), either less complete absorption in the elderly or their higher bodyweight could account for the difference. For celecoxib, AUC(tau) (5.8 +/- 1.7 vs 5.6 +/- 2.3 mg * h/L) and t((1/2)z) (11.8 +/- 8.7 vs 11.2 +/- 2.9 hours) were almost identical in young and older subjects. Plasma protein binding of both NSAIDs was unaffected by age, and apparent oral clearances for unbound drugs were not different between the two groups of healthy subjects. When considering the genotype of all individuals (CYP2C9*1/*1, n = 10; CYP2C9*1/*2, n = 6; CYP2C9*2/*2, n = 2; CYP2C9*1/*3, n = 4; CYP2C9*3/*3, n = 1), no association with any pharmacokinetic parameter of either drug was apparent. Moreover, there was no significant correlation between the AUC values of celecoxib and diclofenac. CONCLUSIONS: Age and CYP2C9 genotype do not significantly affect the steady-state disposition of celecoxib and diclofenac. This would indicate that both drugs need no dosage reduction in the elderly (at least up to 75 years) and that, besides CYP2C9, additional CYP species contribute to the elimination of both agents.

• Effects of celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and elderly subjects.

  Authors: Karin Dilger, Charlotte Herrlinger, Jörg Peters, Hannsjörg W Seyberth, Horst Schweer, Ulrich Klotz

  Journal of clinical pharmacology. 10/2002; 42(9):985-94.

  Cyclooxygenase (COX) inhibitors are among the most widely used drugs, especially in the elderly. It has been claimed that the new COX-2 inhibitors offer advantages in terms of drug safety. To testCyclooxygenase (COX) inhibitors are among the most widely used drugs, especially in the elderly. It has been claimed that the new COX-2 inhibitors offer advantages in terms of drug safety. To test this hypothesis, the authors compared in a double-blind, randomized trial the effects of celecoxib (200 mg bid) and diclofenac (75 mg bid) on blood pressure and renal function in two groups (each n = 12) of young (mean age = 32 years) and elderly (mean age = 68 years) normotensive subjects. Changes from baseline in the 24-hour blood pressure profiles, parameters of the renin-angiotensin-aldosterone system, inulin clearance, urinary marker proteins, and eicosanoid excretion were monitored during the treatment period of 2 weeks. Comparison between celecoxib and diclofenac showed no significant difference in minor alterations of blood pressure. During daytime, there was a trend to elevation of mean arterial blood pressure (mmHg) by celecoxib in the elderly of 2.8 (95 % confidence interval [CI) = -2.5 to 8.2) in comparison with the young subjects of -1.3 (95% CI= -3.7 to 1.0); there was also a trend to elevation of mean arterial blood pressure by diclofenac in the elderly of 4.1 (95% CI= -1.2 to 9.4) in comparison with the young subjects of 0.4 (95% CI= -2.4 to 3.2). In both populations, the authors found no significant drug effects on the parameters of the renin-angiotensin-aldosterone system, inulin clearance, and urinary marker proteins. As expected, diclofenac reduced excretion of allprostanoids, whereas celecoxib did not affect production of TxB2 and its metabolites. Neither in young nor in elderly normotensive subjects were blood pressure and renal function significantly affected by a short-term treatment with standard doses of celecoxib and diclofenac. Therefore, normal aging appears not to represent a special risk factor in therapy with these two agents.

• Budesonide 9 mg Is at Least as Effective as Mesalamine 4.5 g in Patients With Mildly to Moderately Active Crohn's Disease

  Authors: Andreas Tromm, Ivan Bunganič, Eva Tomsová, Zsolt Tulassay, Milan Lukáš, Jan Kykal, Marian Bátovský, Bohumil Fixa, Libor Gabalec, Rifaat Safadi [......] István Altorjay, Hanns Löhr, Ioannis Koutroubakis, Simon Bar–Meir, Davor Štimac, Elke Schäffeler, Christoph Glasmacher, Karin Dilger, Ralf Mohrbacher, Roland Greinwald

  Gastroenterology.

  Background & AimsComparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy inBackground & AimsComparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD.MethodsWe performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L–coated oral mesalamine (4.5 g/day).ResultsThe primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, −4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups.ConclusionsBudesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-L–coated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen.

• Determination of propafenone and its phase I and phase II metabolites in plasma and urine by high-performance liquid chromatography–electrospray ionization mass spectrometry

  Authors: Ute Hofmann, Monika Pecia, Georg Heinkele, Karin Dilger, Heyo K Kroemer, Michel Eichelbaum

  Journal of Chromatography B: Biomedical Sciences and Applications.

  A sensitive method was developed to determine propafenone, 5-hydroxypropafenone, N-despropylpropafenone and propafenone glucuronides in human plasma and urine by HPLC–electrospray ionization massA sensitive method was developed to determine propafenone, 5-hydroxypropafenone, N-despropylpropafenone and propafenone glucuronides in human plasma and urine by HPLC–electrospray ionization mass spectrometry with the respective deuterated analogues as internal standards. The analytes were extracted by a single solid-phase extraction, collecting two fractions, one containing the glucuronides and the other propafenone and the phase I metabolites 5-hydroxypropafenone and N-despropylpropafenone. The mobile phases used for HPLC were: (A) 5 mM ammonium acetate in water and (B) 5 mM ammonium acetate in methanol–tetrahydrofuran (50:50, v/v). Separation of the diastereoisomeric propafenone glucuronides was achieved on a Spherisorb ODS 2 column (150×2.0 mm I.D., particle size 5 μm) at a flow-rate of 0.3 ml/min using a linear gradient from 20% B to 50% B in 15 min. For separation of propafenone, 5-hydroxypropafenone and N-desalkylpropafenone a linear gradient from 50% B to 80% B in 10 min was employed. The mass spectrometer was operated in the selected ion monitoring mode using the respective MH+ ions for quantification. The limits of quantification achieved with this method were 10 pmol/ml for propafenone, 5-hydroxypropafenone, R- and S-propafenone glucuronide and 20 pmol/ml for N-desalkylpropafenone using 0.5 ml of plasma. Reproducibility and accuracy was below 12% for each analyte over the whole concentration range measured. The method was applied to a pharmacokinetic study assessing the influence of rifampicin on propafenone disposition.

• Chronopharmacology of intravenous and oral modified release verapamil

  Authors: Karin Dilger, Klaus Eckhardt, Ute Hofmann, Klaus Kucher, Gerd Mikus, Michel Eichelbaum