Pharmacokinetics of tacrolimus in liver transplant patients*

Jusko, William J.; Piekoszewski, Wojciech; Klintmalm, Göran B.; Shaefer, Mark S.; Hébert, Mary F.; Piergies, Antoni A.; Lee, Charles C.; Schechter, Paul J.; Mekki, Qais

doi:10.1016/0009-9236(95)90153-1

Cited by 216 publications

(187 citation statements)

References 10 publications

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“…The mean time of peak concentration is approximately 1.5 h. The extent of absorp-tion varies considerably (range 5 YO-67 YO). Absorption is bile-independent and not influenced by oral food intake, although fatty meals were found to reduce the bioavailability of tacrolimus [7]. The drug is distributed extensively in the body, and normally most of the drug resides in tissue stores.…”

Section: Introductionmentioning

confidence: 99%

Increased tacrolimus levels during diarrhea

Hochleitner¹,

Bösmüller²,

Nehoda³

et al. 2001

Transplant International

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While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.

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Section: Introductionmentioning

confidence: 99%

Increased tacrolimus levels during diarrhea

Hochleitner¹,

Bösmüller²,

Nehoda³

et al. 2001

Transplant International

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“…[8][9][10][11] Tacrolimus is a large molecule that is highly bound to proteins and to erythrocytes. It is extensively metabolized in the liver primarily through the cytochrome P-450 system.…”

Section: Discussionmentioning

confidence: 99%

Blood tacrolimus concentrations in bone marrow transplant patients undergoing plasmapheresis

Hale

Reece

Munn

et al. 2000

Bone Marrow Transplant

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Summary:Microangiopathic hemolytic anemia (MAHA) is a welldescribed complication of stem cell transplantation. Plasmapheresis is one modality utilized as therapy for patients who develop this complication. However, plasmapheresis may alter whole blood levels of certain medications and its effect on tacrolimus in bone marrow transplant patients is unknown. Because tacrolimus has a narrow therapeutic range, the effect of plasmapheresis on whole blood concentrations would be important to know. We report three allogeneic BMT patients who were receiving tacrolimus as acute GVHD therapy while undergoing plasmapheresis for MAHA. Tacrolimus levels seemed unaffected by plasmapheresis in these patients. Bone Marrow Transplantation (2000) 25, 449-451. Keywords: tacrolimus; plasmapheresis; pharmacokinetics; GVHD; BMT; microangiopathic hemolytic anemia Tacrolimus (FK506) has been studied as a prophylactic and therapeutic agent for acute and chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. 1-3 Tacrolimus has a narrow therapeutic range. Sub-therapeutic levels can lead to inadequate therapy for GVHD while elevated levels can cause unacceptable organ toxicity. 4 Therefore, it is important to be able to anticipate the effect of various interventions so that blood tacrolimus concentrations can be maintained in a therapeutic range. We describe three allogeneic BMT patients who were simultaneously receiving tacrolimus GVHD therapy and plasmapheresis for microangiopathic hemolytic anemia (MAHA) whose tacrolimus levels were unaffected by plasmapheresis. Materials and methodsMAHA was defined according to published criteria, 5 and therapy, including plasmapheresis, was instituted. Acute

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“…However, it is highly variable in solid organ transplant recipients, ranging from 4 to 89% with a mean of 25%. [27][28][29][30] This variability in absorption is not well understood, but may be due to incomplete absorption resulting from poor solubility in gastric fluids, admixture with food, or changes in gut motility and metabolism. 30,31 In liver transplant patients, food reduces the bioavailability of tacrolimus by 27 Ϯ 18.2% when compared to the fasting state.…”

Section: Absorptionmentioning

confidence: 99%

“…27 Therefore, the volume of distribution (V d ) of tacrolimus in plasma and blood is large and variable, ranging from 0.85 to 65 l/kg. [29][30][31]37 Because this variation is partly due to binding of tacrolimus to RBC, the V d determined by whole blood assay is lower than that determined by plasma concentrations. In BMT patients, the whole blood V d was 1.67 Ϯ 1.02 l/kg after a single intravenous dose of 0.02 mg/kg administered over 4 h. 32 …”

Section: Distributionmentioning

confidence: 99%

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

Jacobson

Uberti

Davis

et al. 1998

Bone Marrow Transplant

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Summary:Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

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Pharmacokinetics of tacrolimus in liver transplant patients*

Abstract: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

Cited by 216 publications

References 10 publications

Increased tacrolimus levels during diarrhea

Increased tacrolimus levels during diarrhea

Blood tacrolimus concentrations in bone marrow transplant patients undergoing plasmapheresis

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

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