Biomedical subjects

Tilman Sauerbruch

Publications and source records attributed to Tilman Sauerbruch.

At least 19 recordsLinked to original sources

PubMed2007

Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy.

UNLABELLED: Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486+5G>A resulting in a 54 bp (3465-3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a LOD score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median gamma-glutamyl transpeptidase (gamma-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P = 0.00341). CONCLUSION: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2007

Prevention of recurrent haemorrhage.

Patients who survive a first bleeding episode of oesophageal varices have a high risk of rebleeding, which is associated with a high mortality rate. Prevention of a recurrent haemorrhage is therefore recommended. Patients who were not on a primary prophylaxis should be treated with non-selective beta-adrenoceptor antagonists, endoscopic band ligation or both. If beta-blockers are not tolerated or are contraindicated, patients should be treated with endoscopic band ligation. If these preventive strategies fail, transjugular intrahepatic portosystemic shunt (covered) or a small-diameter surgical shunt is indicated.

Adrenergic beta-Antagonists↗

PubMed2006

C-reactive protein is a prognostic indicator in patients with perihilar cholangiocarcinoma.

AIM: To evaluate prognostic indicators for the outcome of patients with perihilar extrahepatic cholangiocarcinoma in an unselected cohort. METHODS: We retrospectively analyzed 98 patients with perihilar cholangiocarcinoma. Twenty-three patients (23.5%) underwent tumor resection. Patients with non-resectable tumors underwent either transpapillary or percutaneous transhepatic biliary drainage. Additionally, 32 patients (32.7%) received photodynamic therapy (PDT) and 18 patients (18.4%) systemic chemotherapy. Predefined variables at the time of diagnosis and characteristics considering the mode of treatment were entered into a Cox's proportional hazards model. Included in the analysis were age, tumor stage following the modified Bismuth-Corlette classification, bilirubin, prothrombin time (PT), C-reactive protein (CRP), carbohydrate antigen 19-9 (CA19-9), history of weight loss, surgical resection, chemotherapy and PDT. RESULTS: The Kaplan-Meier estimate of overall median survival was 10.5 (95%CI: 8.4-12.6) mo. In the univariate analysis, low Bismuth stage, low CRP and surgical resection correlated significantly with better survival. In the multivariate analysis, only CRP (P = 0.005) and surgical resection (P = 0.029) were found to be independently predictive of survival in the cohort. Receiver operating characteristic (ROC) analysis identified a CRP level of 11.75 mg/L as the value associated with the highest sensitivity and specificity predicting a survival > 5 mo. Applying Kaplan-Meier analysis, patients with a CRP < 12 mg/L at the time of diagnosis had a significantly longer median survival than patients with higher values (16.2 vs 7.6 mo; P = 0.009). CONCLUSION: This retrospective analysis identified CRP level at the time of diagnosis as a novel indicator for the prognosis of patients with perihilar cholangiocarcinoma. It should be evaluated in future prospective trials on this entity.

Adult↗

PubMed2006

Interaction of psychological factors and the effect of epoetin-alfa treatment in cancer patients on hemoglobin and fatigue.

INTRODUCTION AND BACKGROUND: Epoetin alpha is known to produce a hematological response in anemic cancer patients. A concomitant reduction in fatigue as well as an improvement of depression and anxiety and of quality of life has been reported. However, these effects are discussed controversially. Psychological variables may have a moderating effect on fatigue reduction. MATERIALS AND METHODS: Fifty-four anemic cancer outpatients were treated with epoetin alpha over 26 weeks with an initial dose of 3 x 10,000 IU/week and further individually adapted dosage. Hemoglobin level, fatigue, depression, anxiety, and health-related quality of life were measured every 4 weeks. RESULTS: The hematological response rate was 50%, with 1/3 occurring after more than 8 weeks of treatment. Fatigue, depression, and quality of life improved significantly. Reduction in fatigue was associated with response, but the correlations between fatigue and hemoglobin were weak. Less depression and higher quality of life before treatment correlated with a better fatigue reduction when controlling for hemoglobin increase and initial fatigue level. CONCLUSION: Psychological variables influence the reduction of fatigue during therapy with epoetin alpha in anemic cancer patients and should therefore be assessed at the beginning of treatment.

Adult↗

PubMed2006

Induction of interleukin-6 by hepatitis C virus core protein in hepatitis C-associated mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma.

PURPOSE: Chronic hepatitis C carries the risk to develop mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (B-NHL), possibly because viral antigens stimulate the host's inflammatory response via extracellular pattern recognition receptors (PRR). To clarify this issue, we studied whether recognition of hepatitis C virus (HCV) proteins by PRR is involved in the pathogenesis of HCV-associated MC or B-NHL. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells of patients with HCV-associated B-NHL (n = 12), MC (n = 14), uncomplicated hepatitis C (n = 12), and healthy volunteers (n = 12) were incubated with the recombinant HCV proteins E2, core, and NS3 to study induction of cytokine production, stimulation of B-cell proliferation, and immunoglobulin secretion. In addition, serum levels of interleukin-6 (IL-6) were measured by ELISA. RESULTS: HCV core was the only studied protein, which induced production of IL-6 and IL-8 in CD14(+) cells. IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro. TLR2 expression on monocytes and IL-6 serum concentrations were increased in all groups of HCV-infected patients compared with healthy controls and were highest in MC (P < 0.05). CONCLUSIONS: Increased secretion of IL-6 via stimulation of TLR2 by HCV core protein may play a role in the pathogenesis of hepatitis C-associated MC and B-NHL.

Adult↗

PubMed2006

Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model.

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, and new alternative treatments are needed. AIMS: To comparatively test the angiostatic and antitumour effects of adenoviral gene transfer of angiostatin (PlgK1-4, amino acids 1-440) and full kringles 1-5 (PlgK1-5, amino acids 1-546) in a model of subcutaneously transferred HCC in mice. METHODS: PlgK1-4 and PlgK1-5 were generated from human WtPlg cDNA and used for adenovirus construction. Vector function and angiostatic effects were confirmed in vitro and in vivo. Antitumoral efficacies of intratumoral vector injections were studied in a model of subcutaneously transferred HCC model. RESULTS: Cell supernatants containing PlgK1-4 and PlgK1-5 reduced endothelial tube formation in vitro by about 30%, whereas WtPlg exerted no inhibitory effect. Endothelial cell infiltration in vivo was decreased by about 60%, but not in AdWtPlg-treated animals. Intratumoral treatment of subcutaneous HCC tumours inhibited growth by 40% for AdPlgK1-4 and 63% for AdPlgK1-5 in surviving mice 12 days after initiation of treatment, whereas treatment with AdWtPlg even led to accelerated growth. Although PlgK1-4 and PlgK1-5 have similar inhibitory effects on intratumoral microvessels, PlgK1-5 markedly improved the survival time compared with PlgK1-4. CONCLUSION: PlgK1-5 and PlgK1-4 effectively inhibited HCC growth. As PlgK1-5 could also prolong the survival time, inducing complete tumour elimination in half of the AdPlgK1-5-treated mice, PlgK1-5 might be the most potential plasminogen fragment for treatment of experimental HCC.

Angiogenesis Inhibitors↗

PubMed2006

Combination of systemic thioacetamide (TAA) injections and ethanol feeding accelerates hepatic fibrosis in C3H/He mice and is associated with intrahepatic up regulation of MMP-2, VEGF and ICAM-1.

BACKGROUND/AIMS: The induction of liver fibrosis is difficult in mice. Here, we intended to improve fibrosis induction by combination of thioacetamide (TAA) injections and ethanol (EtOH) feeding and to characterize features of liver damage in this model. Most experimental therapeutic studies are performed in mice without pre-damaged livers. METHODS: C3H mice were injected three times/week (0.15 mg/g body weight) and fed with EtOH. Tissue and serum samples were collected and analysed. RESULTS: Portal fibrosis was verified by van Gieson staining showing a mild fibrosis (score F2) in TAA-treated mice and liver fibrosis (score F4) in the combination group using TAA/EtOH. Consonant with the histological results, the fibrosis marker MMP-2 and alpha 1 procollagen (I) were elevated at week 10 and 15 after treatment initiation in the combination group, whereas tissue protective proteinase, TIMP-1, was 18.5-fold increased only at week 10 but normalized until week 15. Fibrosis development was associated with elevated ICAM-1 expression. CONCLUSIONS: Taken together, TAA/EtOH application was suitable to induce liver fibrosis characterized by typical bio-markers in C3H/He.

Animals↗

PubMed2006

Cholecystitis in neutropenic patients: retrospective study and systematic review.

Abdominal infections are life-threatening complications in neutropenic patients. Among these, neutropenic cholecystitis is relatively rare. Nevertheless, its actual relevance is only investigated by anecdotal reports. We present a consecutive retrospective series of nine patients over a 12-year period. We calculated a frequency of 0.4% among all neutropenic episodes in patients with acute leukemia or aggressive lymphoma undergoing myelosuppressive chemotherapy. Only three of these patients had gallstones. Four patients died during the course of cholecystitis but in none of them cholecystitis was the primary cause of death. Systematic review of the literature revealed 45 patients with neutropenic cholecystitis of whom 26.7% died.

Acute Disease↗

PubMed2006

Presentation of the HCV-derived lipopeptide LP20-44 by dendritic cells enhances function of in vitro-generated CD4+ T cells via up-regulation of TLR2.

In vitro immunization with HCV lipopeptide aa 20-44 results in antigen-specific T cells. Here, we studied whether presentation of the lipopeptide by dendritic cells (DC) results in enhanced T cell functions. DC-immunized T cells showed significantly augmented proliferation and IFN-gamma secretion upon HCV-specific re-stimulation. This effect was related to significantly increased expression of TLR2 on DC-immunized CD4+ T cells and required TLR2 triggering during re-stimulation. In contrast, numbers of HLA-A2-pentamer-positive CD8+ T cells and granzyme B-secreting T cells remained unchanged. Thus, up-regulation of TLR2 during immunization with DC enhances functions of CD4+ T cells but not CD8+ T cells.

Adjuvants, Immunologic↗

PubMed2006

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure.

Previously, we demonstrated that intrahepatic upregulation of the immunoactivating molecules CD40 and CD40 ligand (CD40L) are early mechanisms for liver cell damage in human and murine fulminant hepatic failure (FHF). In the present study, we investigated the functional effects of intrahepatic overexpression of CD40L by adenoviral-mediated gene transfer (AdCD40L) in mice. AdCD40L injection induced severe liver cell damage, which was associated with increased alanine aminotransferase (ALT) levels peaking at day 5 after vector administration (AdCD40L, 1,707 +/- 279 U/L; AdLacZ, 213 +/- 25 U/L) and with lethality in half of the mice. Except for mild splenomegaly, no organs other than the liver were involved in inflammatory reactions. CD40-CD40L interaction was mandatory for liver damage, because CD40(-/-) mice were completely protected. Furthermore, CD40L-induced FHF depended on competent lymphocytes, because inflammatory reactions were strongly decreased in SCID and Rag1(-/-) mice. In contrast, neither natural killer T (NKT) cells nor Kupffer cells relevantly influenced histology as shown in NKT cell-deficient CD1d(-/-) mice and by gadolinium depletion of Kupffer cells. Furthermore, immunosuppression by dexamethasone and cyclosporin A was not sufficient to block CD40L damage. In conclusion, we present a model of FHF with strong similarities to human FHF with respect to time course and histological changes. This model suggests involvement of the CD40-CD40L system in FHF and might have important implications for future pathophysiological studies of this condition.

Adenoviridae↗

PubMed2006

Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C.

Dendritic cells (DC) are crucially involved in the induction of immune responses; however, reports on DC functions in chronic hepatitis C are controversial. Function of DC includes proper cell trafficking between sites of infection and lympho-cellular compartments. Thus, we analyzed DC compartmentalization and changes in DC migration in hepatitis C virus (HCV)-infected patients. We found significantly lower numbers of circulating BDCA1+ and BDCA2+ DC in HCV(+) patients (n = 20) than in healthy controls (n = 12) (P < .05). Analyzing liver samples from HCV(+) patients (n = 15), HCV(-) controls (n = 15), and disease controls (n = 10), we demonstrated chronic hepatitis C to be associated with intrahepatic DC enrichment (P < .05). In vitro studies indicated that HCV E2-induced secretion of RANTES efficiently attracts CCR5(+) immature DC. Incubation of DC with sera derived from HCV(+) patients made DC unresponsive to CCL21, the chemokine recruiting DC to lymphoid tissues for T cell priming. Unlike attraction of CCR5+ DCs via RANTES, direct inhibition of DC migration in response to CCL21 was specific for patients with chronic hepatitis C and could be attributed to interaction of HCV E2 with CD81 on DC. In conclusion, migration of DC is markedly affected by interaction of HCV E2 with CD81. Failure of DC to recirculate to lymphoid tissue may be critically involved in impaired T cell priming during HCV infection.

Adult↗

PubMed2006

Estimation of glomerular filtration rates after orthotopic liver transplantation: Evaluation of cystatin C-based equations.

Early detection of renal dysfunction in patients after orthotopic liver transplantation is important. Creatinine-based equations to estimate glomerular filtration rate (GFR) were found to be less accurate in liver transplant recipients than in their original populations. Since cystatin C (CysC) is independent from muscle mass and hepatic biosynthesis, we evaluated the diagnostic accuracy of 3 CysC-based equations (Larson, Hoek, and Filler formulae) that are based on the same CysC method as that of our center in comparison to the abbreviated creatinine-based modification of diet in renal disease (MDRD) formula in 59 liver transplant recipients. "True GFR" was measured by 99mTc-diethylene triamine pentaacetic acid ((99m)Tc-DTPA) clearance. Neither correlation with the GFR (correlation coefficients: 0.594-0.640) nor precision (root mean square error: 15.7-18.17 mL/min/1.73 m(2)) differed significantly between the tested formulae. The biases of the Hoek and Larsson formulae were significantly smaller than those of the MDRD and Filler equations (-0.1 and -2.3 vs. 10.1 and 7.9 mL/min/1.73 m(2), respectively; P </= 0.0023). Mean estimates of MDRD (61.9 +/- 21.4 mL/min/1.73 m(2)) and Filler (61.2 +/- 22.1 mL/min/1.73 m(2)) differed significantly from the measured GFR (52.3 +/- 17.5 mL/min/1.73 m(2); P < 0.005), whereas Larsson and Hoek did not (49.5 +/- 20.2 and 51.4 +/- 17.9 mL/min/1.73 m(2), respectively). Accuracy within 30% and 50% of the true GFR was best for the Hoek (76.3% and 93.2%) formula, albeit not significantly different from MDRD (64.4% and 83.1%). Taken together, these data show the best overall performance for GFR estimates derived from the Hoek equation with respect to bias, precision, and accuracy.

Adult↗

PubMed2006

Intestinal oxalate absorption is higher in idiopathic calcium oxalate stone formers than in healthy controls: measurements with the [(13)C2]oxalate absorption test.

PURPOSE: We assessed the importance of oxalate hyperabsorption for idiopathic calcium oxalate urolithiasis, oxalate absorption in healthy volunteers and recurrent calcium oxalate stone formers was compared. MATERIALS AND METHODS: The [(13)C2]oxalate absorption test, a standardized, radioactivity-free test, was performed. On 2 days 24-hour urine was collected and an identical standard diet containing 800 mg Ca daily was maintained. On the morning of day 2 a capsule containing 0.37 mmol sodium [(13)C2]oxalate was ingested. A total of 120 healthy volunteers (60 women and 60 men) and 120 patients (30 women and 90 men) with idiopathic CaOx urolithiasis (60% or greater CaOx) were tested. RESULTS: Mean intestinal oxalate absorption in the volunteers was 8.0 +/- 4.4%, and in the patients was 10.2 +/- 5.2% (p <0.001). There was no significant difference in mean absorption values between men and women within both groups. A high overlap between the absorption values of volunteers and patients was found. Only in the patient group did absorption values greater than 20% occur. Oxalate absorption correlated with oxalate excretion in the patients, r = 0.529 (p <0.01) and in the volunteers, r = 0.307 (p <0.01). CONCLUSIONS: In high oxalate absorbers dietary oxalate has a significant role in oxalate excretion and, therefore, increases the risk of calcium oxalate stone formation.

Adolescent↗

PubMed2006

Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats.

BACKGROUND & AIMS: Portal hypertension is associated with arterial hypotension and vascular hypocontractility, which persists despite elevated plasma levels of vasoconstrictors. We investigated the role of the RhoA/Rho-kinase pathway in vascular smooth muscle hypocontractility of rats with secondary biliary cirrhosis. METHODS: Aortic expressions of RhoA and Rho-kinase were analyzed in sham-operated and BDL rats by reverse-transcription polymerase chain reaction (RT-PCR) and immunoblots. Activation of aortic RhoA was examined by pull down of guanosine triphosphate (GTP)-RhoA and membrane translocation of RhoA. Rho-kinase activity was assessed as phosphorylation of its substrate, moesin. Contractility of isolated aortic rings was determined myographically. The hemodynamic effect of the Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) was determined in vivo by measuring changes in mean arterial pressure and systemic vascular resistance (SVR) (microspheres). RESULTS: Contraction of aortic rings from BDL rats was impaired in response to the alpha(1)-adrenergic receptor agonist methoxamine but not to high molar KCl. Aortic expression of RhoA was unchanged in cirrhotic rats, whereas Rho-kinase was down-regulated posttranscriptionally. Methoxamine-induced activation of RhoA as well as basal and methoxamine-induced phosphorylation of moesin were strongly reduced in aortas from cirrhotic rats. Aortic rings from cirrhotic rats precontracted with methoxamine showed an increased sensitivity to relaxation with Y-27632. The drop in SVR induced by Y-27632 was larger in cirrhotic rats than in sham-operated rats. CONCLUSIONS: An impaired vascular activation of RhoA and a down-regulation of Rho-kinase might contribute to vasodilation and vascular hypocontractility in BDL-induced cirrhosis.

Amides↗

PubMed2006

Circadian rhythm of fasting and postprandial portal blood flow in cirrhosis.

OBJECTIVE: To examine the relationship of both the unstimulated and the postprandial portal blood flow (PVF) to the time of day and to determine its intra-individual reproducibility over time in patients with liver cirrhosis. MATERIAL AND METHODS: In 24 cirrhotic patients, 27 PVF measurements were performed during 24 h on day 0 and day 7 using Doppler ultrasound. Three standard liquid meals were given orally. On day 7, the baseline hepatic venous pressure gradient (HVPG) was also measured. RESULTS: Circadian area under the time curve of PVF was highly reproducible within individuals (r=0.959, p<0.001). It did not correlate with HVPG. Cosinor analysis showed a significant circadian rhythm of PVF (acrophase at 11:44 and amplitude of 9.44%). Maximal postprandial increase in PVF was significantly higher in the morning than at noon or in the evening. CONCLUSIONS: PVF is subject to a circadian rhythm and postprandial portal hyperemia shows a diurnal variability. Both are highly reproducible.

Circadian Rhythm↗

PubMed2006

Total ascitic fluid leukocyte count for reliable exclusion of spontaneous bacterial peritonitis in patients with ascites.

BACKGROUND AND AIMS: The diagnosis of spontaneous bacterial peritonitis (SBP) in patients with ascites is established by definition with a polymorphonuclear (PMN) cell count in the ascitic fluid greater than 0.250 g/l determined via cytological (microscopic) examination. In this study, we correlated the automatically assessed total ascitic nucleated cell count with PMN and determined its predictive value for diagnosis of SBP. METHODS: Six hundred and eleven consecutive paracenteses of 179 patients with ascites of various aetiologies (liver cirrhosis, hepatocellular carcinoma, peritoneal carcinomatosis, and ascites of other aetiology) were studied retrospectively. RESULTS: The most reliable diagnostic cut-off level was determined for differentiation between SBP and non-SBP via receiver operating characteristics analysis. A total ascitic nucleated cell count less than 1.0 g/l is unlikely to represent SBP (negative predictive value, 95.5%). CONCLUSIONS: If ascitic fluid samples with machine-made total ascitic nucleated cell count below 1.0 g/l are not followed by additional laboratory tests, the risk of missing the diagnosis of SBP is low. Applying these criteria we would have classified 51 samples of 611 samples (20 of 179 patients) wrongly using the cut-off value of 1 g/l. On the other hand we would have spared cytologic evaluation in about 63% of paracentesis performed in our hospital. Nevertheless, to insure patient safety, standard laboratory analysis is recommended in circumstances of clinical uncertainty. Thus, patients with first manifestation of ascites should always receive cytologic examination and full diagnostic investigation to exclude other causes of ascites.

Adult↗

PubMed2006

Pseudomembranous and obstructive Aspergillus tracheobronchitis - optimal diagnostic strategy and outcome.

Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10-year period (1995-2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non-ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately.

Adult↗

PubMed2006

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

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 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.

Administration, Oral↗