Protopic
Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: Consequences for FK506 assimilation.

Lemahieu WP, Maes BD, Verbeke K, Vanrenterghem Y.

Division of Nephrology and Laboratory of Digestion and Absorption, Department of Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium.

Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: Consequences for FK506 assimilation. Background. Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) are important determinants of the oral bioavailability and clearance of tacrolimus. Cimetidine and omeprazole are known modulators of several CYPs in vitro. In the present study, the impact of cimetidine and omeprazole on tacrolimus exposure and on CYP3A4/PGP activity in vivo was examined. Methods. In a cohort of 48 renal transplant recipients who switched standard ulcer prophylaxis with 400 mg of cimetidine daily to 20 mg of omeprazole, dose/weight normalized trough levels of tacrolimus during a 5-day interval before and after switch were compared and further studied using multivariate analysis. In a cohort of 6 healthy volunteers, the effect of a 5-day course of ranitidine, cimetidine, and omeprazole on overall CYP, CYP3A4, and PGP activity in vivo was assessed with the (13)C-aminopyrin breath test and the combined per oral and intravenous (14)C-erythromycin breath and urine test. Results. Dose/weight normalized trough levels of tacrolimus decreased significantly (-15%) after switch from cimetidine to omeprazole. In healthy volunteers, a significant increase of intestinal CYP3A4 activity was observed after omeprazole, whereas no change was noted after cimetidine/ranitidine. Overall CYP activity was significantly decreased after cimetidine and remained unchanged after omeprazole/ranitidine. No effects on PGP or hepatic CYP3A4 were seen. Conclusion. Switching treatment with cimetidine to omeprazole in renal transplant recipients is associated with a decrease of dose/weight normalized trough levels of tacrolimus. Studies in healthy volunteers suggest that this may be explained by an increase of intestinal CYP3A4 activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15698457&dopt=Abstract tacrolimus Protopic



Protopic
Overview of tacrolimus-based immunosuppression after heart or lung transplantation.

Reichenspurner H.

Department of Cardiovascular Surgery, University Hospital-Eppendorf, Hamburg, Germany. hcr uke.uni-hamburg.de

Transplantation has evolved into an accepted treatment for end-stage heart or lung disease. Acute rejection, complications related to immunosuppressive protocols, and the development of chronic rejection continue to challenge the long-term success of heart and lung transplantations. Wide acceptance of tacrolimus as an important immunosuppressant in renal and hepatic transplantations has led subsequently to its investigation as primary immunosuppression in heart and lung transplant recipients, either combined with azathioprine or with the newer agents mycophenolate mofetil or rapamycin. Studies have shown that tacrolimus is an effective therapeutic alternative to cyclosporine for primary immunosuppression in heart or lung transplantation and demonstrates equivalent if not improved prophylaxis of acute rejection, and more recently demonstrates a potential influence on chronic rejection, particularly in lung transplant recipients. Of importance, the enhanced immunosuppressive activity of tacrolimus is achieved without increased risk of infection or malignancy. Differences in tolerability profiles and side effects between tacrolimus and cyclosporine may be used in selecting the optimal immunotherapy after thoracic transplantation. In particular, the lesser propensity of tacrolimus to cause hypertension and hyperlipidemia potentially offers decreased cardiovascular risk for heart and lung transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15701425&dopt=Abstract tacrolimus Protopic



Protopic
The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level.

Oetjen E, Thoms KM, Laufer Y, Pape D, Blume R, Li P, Knepel W.

1Department of Molecular Pharmacology, University of Gottingen, D-37099 Gottingen, Germany.

Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs directly targeting the transcription factor nuclear factor of activated T cells (NFAT). Through inhibition of calcineurin phosphatase activity they block the dephosphorylation and thus activation of NFAT. Cyclosporin A and tacrolimus also inhibit other calcineurin-dependent transcription factors including the ubiquitously expressed cAMP response element-binding protein (CREB). Membrane depolarization by phosphorylating CREB on Ser119 leads to the recruitment of its coactivator CREB-binding protein (CBP) that stimulates initiation of transcription.It was unknown at what step in CREB-mediated transcription cyclosporin A and tacrolimus interfere.In transient transfection experiments, using GAL4-CREB fusion proteins and a pancreatic islet beta-cell line, cyclosporin A inhibited depolarization-induced activation of CREB proteins which carried various deletions or mutations throughout their sequence providing no evidence for the existence of a distinct CREB domain conferring cyclosporin A sensitivity. In a mammalian two-hybrid assay, cyclosporin A did not inhibit Ser119-dependent interaction of CREB with its coactivator CBP.Using GAL4-CBP fusion proteins, cyclosporin A inhibited depolarization-induced CBP activity, with cyclosporin A-sensitive domains mapped to both the N- (aa 1-451) and C-terminal (aa 2040-2305) ends of CBP. The depolarization-induced transcriptional activity of the CBP C-terminus was enhanced by overexpression of calcineurin and was inhibited by cyclosporin A and tacrolimus in a concentration-dependent manner with IC(50) values (10 and 1 nM, respectively) consistent with their known IC(50) values for inhibition of calcineurin.These data suggest that, in contrast to NFAT, cyclosporin A and tacrolimus inhibit CREB transcriptional activity at the coactivator level.British Journal of Pharmacology advance online publication, 14 February 2005; doi:10.1038/sj.bjp.0706127.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15711594&dopt=Abstract tacrolimus Protopic



Protopic
Clinical significance of hematocrit interference in the tacrolimus II microparticle enzyme immunoassay: a tentative approach.

Hermida J, Fernandez MC, Tutor JC.

Laboratorio Central, Hospital Clinico Universitario, Santiago de Compostela, Spain.

Recently, the possible interference of hematocrit on the results of the Abbott Tacrolimus II microparticle enzyme immunoassay (MEIA) has been described, although its significance in clinical practice has not been established as yet. The aim of our study was the evaluation of the significance of this analytical interference in therapeutic tacrolimus monitoring. In 1121 cases selected at random over a 9-month period from kidney (n=379) and liver (n=742) transplant patients, an estimation was made of errors caused by the hematocrit in the results provided by the Tacrolimus II MEIA. In accordance with the available data, it was assumed that an error may be produced beyond the range of hematocrit values from 30% to 40%, either positive or negative respectively, of 3% per unit of hematocrit. The acceptance criterion for accuracy was no more than 15% of deviation (error) with respect to the experimental concentration of tacrolimus. In 160 cases (14.3%) the results of the Tacrolimus II MEIA would not be acceptable due to hematocrit-dependent errors, both with positive (hematocrit <25%) in 108 cases (9.7%) and negative values (hematocrit >45%) in 52 cases (4.6%). The obtained results demonstrate the practical interest of the subject, although additional studies are required in order to validate our approach to the clinical significance of this hematocrit-dependent interference in the Tacrolimus MEIA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15719703&dopt=Abstract tacrolimus Protopic



Protopic
A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis.

Miyata S, Ohkubo Y, Mutoh S.

Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka, 532-8514, Japan. susumu_miyata po.fujisawa.co.jp

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15723198&dopt=Abstract tacrolimus Protopic



Protopic
Treatment of localized lesions of canine atopic dermatitis with tacrolimus ointment: a blinded randomized controlled trial.

Bensignor E, Olivry T.

Dermatology Unit, Veterinary Clinic, 75003 Paris and 35510 Cesson-Sevigne, France.

Abstract This investigator-blinded randomized controlled trial was designed to determine whether tacrolimus ointment (Protopic, Fujisawa Healthcare) decreased the severity of localized lesions of canine atopic dermatitis (AD). Twenty dogs with AD were enrolled if they exhibited lesions on both front metacarpi. Each foot was randomized to be treated with 0.1% tacrolimus or placebo (vaseline) ointment twice daily for 6 weeks. Before, and every 2 weeks during the study, erythema, lichenification, oozing and excoriations each were graded on a 10-point scale (maximal total score: 40). The primary outcome measures were the percentage reduction from baseline of lesional scores and the number of subjects whose scores had decreased by 50% or greater at study end. Intention-to-treat analyses were used. At study onset, lesional scores were not significantly different between sites treated with tacrolimus or placebo. After 6 weeks, the percentage reduction from baseline scores was higher for tacrolimus-treated sites (median: 63%; 95% confidence interval: 39-67) than for placebo-treated feet (median: 3%; confidence interval: -2-13) (Wilcoxon test; P = 0.0003). When tacrolimus was applied, lesions decreased by 50% or greater in 15/20 dogs (75%); these dogs were those that completed the study. In contrast, this benchmark was not reached for any placebo-treated feet (Fisher's test; P < 0.0001). Adverse drug events consisted of minor irritation in some lesional areas treated with tacrolimus. Results of this trial suggest that the application of 0.1% tacrolimus ointment is useful for reducing the severity of localized skin lesions of canine AD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15725106&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians.

Macphee IA, Fredericks S, Mohamed M, Moreton M, Carter ND, Johnston A, Goldberg L, Holt DW.

Cellular and Molecular Medicine, Renal Medicine, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. imacphee sghms.ac.uk

Previously, we demonstrated that the dose-normalized tacrolimus blood concentration after renal transplantation was associated with a single nucleotide polymorphism (SNP) in the CYP3AP1 gene, probably through linkage with an SNP in the CYP3A5 gene. Individuals with at least one CYP3A5*1 allele synthesize CYP3A5 and CYP3A5*3/*3 homozygotes do not. We now present results with direct typing of the CYP3A5 genotype for this group of 180 kidney-only transplant recipients from a single center. South Asian and white patients with at least one CYP3A5*1 allele achieved twofold lower dose-normalized tacrolimus blood concentrations compared with CYP3A5*3/*3 homozygotes, confirming our previous findings for the CYP3AP1 SNP. There was a significant delay in achieving target blood concentrations in those with at least one CYP3A5*1 allele. Determination of the CYP3A5*1/*3 genotype could be used to predict the tacrolimus dose requirement and, given incomplete linkage, would be better than determination of the CYP3AP1 genotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15729180&dopt=Abstract tacrolimus Protopic