Protopic
High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association criteria.

Cho YM, Park KS, Jung HS, Jeon HJ, Ahn C, Ha J, Kim SJ, Rhee BD, Kim SY, Lee HK.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

OBJECTIVE: The incidence of posttransplantation diabetes mellitus (PTDM) has been reported to vary according to different study populations or different definitions. In this study, using American Diabetes Association criteria, the incidence and clinical characteristics of PTDM in Korean renal allograft recipients undergoing tacrolimus-based immunosuppression were examined. RESEARCH DESIGN AND METHODS: A total of 21 patients taking tacrolimus as primary immunosuppressant were recruited and tested with a serial 75-g oral glucose tolerance test at 0, 1, 3, and 6 months after renal transplantation. RESULTS: The cumulative incidence of PTDM was 52.4% at 1 month and 57.1% at 3 and 6 months. The baseline characteristics of the PTDM group were old age (especially >40 years), a high BMI, a high fasting glucose level, a high plasma insulin level, and increased insulin resistance. Among these parameters, old age was the only independent risk factor. The insulin secretory capacity in the PTDM group was maximally suppressed 3 months after transplantation. Thereafter, it was gradually restored along with dose reduction of tacrolimus. CONCLUSIONS: Routine screening for PTDM is necessary in patients over 40 years of age who are undergoing a relatively higher dose tacrolimus therapy during the early course of postrenal transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12663584&dopt=Abstract tacrolimus Protopic



Protopic
Cost-effectiveness analysis of tacrolimus ointment versus high-potency topical corticosteroids in adults with moderate to severe atopic dermatitis.

Ellis CN, Drake LA, Prendergast MM, Abramovits W, Boguniewicz M, Daniel CR, Lebwohl M, Paller AS, Stevens SR, Whitaker-Worth DL, Tong KB.

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109-0314, USA.

BACKGROUND: Few cost-effectiveness analyses have been conducted on topical therapies for atopic dermatitis. OBJECTIVE: We sought to compare cost-effectiveness of high-potency topical corticosteroids (HPTCs) and tacrolimus ointment for the treatment of moderate to severe atopic dermatitis for patients who are not responsive to or not well controlled with mid-potency topical corticosteroids. METHODS: A Markov model represented the cyclic nature of atopic dermatitis. Clinical outcomes were derived from published literature. "Efficacy" was defined as disease-controlled days on which patients experienced a greater than 75% improvement in their disease. Resource use and changes in management were on the basis of opinions of a physician panel; secondary treatment was an oral antibiotic with topical corticosteroids. Sensitivity analyses were conducted for all variables. RESULTS: The model was sensitive to duration of continuous treatment with HPTCs. HPTCs, when limited to 2-week treatment cycles, were associated with the highest total costs ($1682 per year) and the least efficacy (185 disease-controlled days). HPTCs in 4-week treatment intervals and tacrolimus ointment were similar in total costs and efficacy ($1317 vs $1323 for 194 vs 190 disease-controlled days, respectively). Although primary drug costs were higher for patients treated with tacrolimus ointment, patients treated with regimens of HPTCs incurred higher secondary drug costs. CONCLUSION: In the base case analyses, tacrolimus ointment was more cost-effective than HPTCs administered in 2-week treatment cycles, and similar in cost-effectiveness to 4-week cycles of HPTCs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12664019&dopt=Abstract tacrolimus Protopic



Protopic
[Expression of nuclear factor kappaB and the effect of topical tacrolimus ointment on lesional atopic dermatitis skin.]

[Article in Chinese]

Xie ZQ, Liu LL, Dou X, Wen WJ, Wang D, Zhu XJ.

Department of Dermatology, Peking University First Hospital, Beijing 100034, China.

OBJECTIVE: To investigate the role of nuclear factor kappaB (Rel/NF-kappaB) in pathogenesis of atopic dermatitis(AD) and the effect of topical 0.1%(mass fraction) or 0.03%(mass fraction) tacrolimus ointment on expression of NF-kappaB in lesional AD skin. METHODS:Immunohistochemistry has been employed to study the expression of NF-kappaB in normal skin and lesional AD skin before and after using topical tacrolimus ointment. RESULTS: The expressions of NF-kappaBp50 and NF-kappaBp65 were scattering or negative in normal keratinocytes. NF-kappaBp50 was overexpressed on nuclear of basal and suprabasal keratinocytes in 9 cases of AD, NF-kappaBp65 was overexpressed in cytoplasm and perinuclear of basal and suprabasal keratinocytes. After using topical tacrolimus ointment for three weeks , nuclear NF-kappaBp50 expressed on basal and suprabasal keratinocytes were lost and NF-kappaBp50 was expressed sparsely on basal keratinocytes cytoplasm or nuclear. NF-kappaBp65 was expressed sparsely on basal and suprabasal keratinocytes cytoplasm. CONCLUSION: These data suggest that increased NF-kappaB activity may represent the basis of initiation or maintenance of the skin inflammatory response in atopic dermatitis. Topical tacrolimus may directly or indirectly inhibit NF-kappaB nuclear expression in keratinocytes and inhibit skin innate immuno-inflammatory response in atopic dermatitis that related to NF-kappaB.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15489928&dopt=Abstract tacrolimus Protopic



Protopic
The site-specific transport and metabolism of tacrolimus in rat small intestine.

Tamura S, Tokunaga Y, Ibuki R, Amidon GL, Sezaki H, Yamashita S.

Fujisawa Pharmaceutical Co., Ltd., 1-6 Kashima 2-Chome, Yodogawa-ku, Osaka, Japan 532-8514. shigeki_tamura po.fujisawa.co.jp

The objective of this study was to evaluate the absorption of tacrolimus by means of simultaneous perfusion of intestinal lumen and blood vessels in rats. In our previous report, the permeability of tacrolimus was found to be higher in the jejunum than in the ileum or colon, suggesting the site-dependent absorption after oral administration. However, in this article, simultaneous perfusion technique revealed that the extent of absorption into blood vessels was similar in the jejunum and the ileum regardless of the site difference in permeability as the absorption rate. In addition to the multidrug resistance-associated protein-mediated efflux, cytochrome P450 (P450)-mediated metabolism could be a possible mechanism to explain the inconsistencies in the site dependence of tacrolimus absorption. Two enzyme inhibitors, ketoconazole and midazolam, were coperfused in rat intestinal lumen with tacrolimus to specify the effect of P-gp and P450. In the jejunum, both inhibitors significantly enhanced the absorbed amount of tacrolimus, whereas the permeability was not affected. It was suggested that both inhibitors mainly suppress P450-mediated metabolism in the upper region of the intestine. In contrast, in the ileum, ketoconazole significantly enhanced both the absorbed amount and the permeability of tacrolimus. However, midazolam failed to enhance the absorption of tacrolimus, indicating the dominant role of P-glycoprotein (P-gp)-mediated efflux in the lower region. From these findings, it is concluded that the site-dependent differences in P-gp and/or P450 activity could be the prime cause of large intra- and interindividual variability in the oral absorption of tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12676880&dopt=Abstract tacrolimus Protopic



Protopic
In vitro effects of tacrolimus on human cytochrome P450.

Lecointre K, Furlan V, Taburet AM.

Toxicology laboratory, C.H.U. de Bicetre, AP/HP. 78 rue du General Leclerc, 94270 Kremlin-Bicetre, France.

Tacrolimus, a potent immunosuppressive drug, is known to be metabolized predominantly in the liver by cytochrome P450 3A (CYP3A). In order to determine the potential of tacrolimus to inhibit the metabolism of other drugs, we have investigated its inhibitory effects on specific cytochrome reactions. Specific substrates for the seven cytochromes (CYPs) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4/5 were incubated with human hepatic microsome preparations with or without specific inhibitors or tacrolimus and the metabolites were detected by high-pressure liquid chromatography (HPLC) or fluorimetric methods. All the specific inhibitors reduced or abolished the specific CYP activity. Tacrolimus had no effect on any CYP at concentrations below 1 microM, while at higher concentrations it had a mild inhibitory effect on CYP3A4 and 3A5. These observations suggest that tacrolimus is unlikely to potentiate the effect of coadministered drugs through inhibition of their metabolism in the liver.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12685503&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms.

Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ.

Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA, USA.

Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12694072&dopt=Abstract tacrolimus Protopic



Protopic
Determination of risk factors for Epstein-Barr virus-associated posttransplant lymphoproliferative disorder in pediatric liver transplant recipients using objective case ascertainment.

Guthery SL, Heubi JE, Bucuvalas JC, Gross TG, Ryckman FC, Alonso MH, Balistreri WF, Hornung RW.

Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. Stephen.Guthery hsc.utah.edu

BACKGROUND: Previous studies have suggested an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder (EBV-PTLD) in patients receiving tacrolimus for immunosuppression. We hypothesized that after correction for confounding variables, immunosuppression with tacrolimus is not associated with an increased risk of EBV-PTLD. METHODS: Potential cases of EBV-PTLD, identified by chart review, were independently ascertained by three clinicians and defined using published criteria. Agreement in diagnosing EBV-PTLD was measured using Kappa coefficients. Unadjusted and adjusted relative risk estimates were determined using proportional hazards regression. RESULTS: Twenty-three cases of EBV-PTLD were identified in 221 patients, a proportion of 10.4% (95% confidence interval [CI]: 6.4%-14.4%). Multivariable analysis revealed that immunosuppression with tacrolimus was associated with an increased risk of EBV-PTLD (relative risk 3.10: 95% CI: 1.21-7.92), as was age at transplantation as a continuous variable (parameter estimate -0.15, P=0.03). Kappa coefficients in diagnosing EBV-PTLD and subclassifying as neoplastic and non-neoplastic EBV-PTLD were 0.73 (95% CI: 0.54-0.93) and 0.54 (95% CI: 0.40-0.68), respectively. Patients with neoplastic PTLD demonstrated a lower probability of survival than patients with non-neoplastic PTLD and non-cases. CONCLUSIONS: Immunosuppression with tacrolimus and young age at transplantation are associated with an increased risk of EBV-PTLD in children undergoing liver transplantation, although we cannot exclude detection bias as an explanation for this observed increase. Good agreement between observers can be achieved using previously published criteria for defining EBV-PTLD. Patients with neoplastic EBV-PTLD may have a worse prognosis, and thus identification of risk factors for the development of this subtype of the disorder may be more important.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12698085&dopt=Abstract tacrolimus Protopic