Clinical Pharmacokinetics of Tacrolimus

Raman Venkataramanan, Arun Swaminathan, Tata Prasad, Ashok Jain, Sheila Zuckerman, Vijay Warty, John McMichael, Jacqueline Lever, Gilbert Burckart, Thomas Starzl

Research output: Contribution to journalReview article

550 Citations (Scopus)

Abstract

Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and α1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.

Original languageEnglish (US)
Pages (from-to)404-430
Number of pages27
JournalClinical Pharmacokinetics
Volume29
Issue number6
DOIs
StatePublished - Dec 1995

Fingerprint

Tacrolimus
Pharmacokinetics
Pharmaceutical Preparations
Drug Monitoring
Lactones
Immunosuppressive Agents
Drug Interactions
Capsules
Half-Life
Albumins
Glycoproteins
Erythrocytes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Venkataramanan, R., Swaminathan, A., Prasad, T., Jain, A., Zuckerman, S., Warty, V., ... Starzl, T. (1995). Clinical Pharmacokinetics of Tacrolimus. Clinical Pharmacokinetics, 29(6), 404-430. https://doi.org/10.2165/00003088-199529060-00003
Venkataramanan, Raman ; Swaminathan, Arun ; Prasad, Tata ; Jain, Ashok ; Zuckerman, Sheila ; Warty, Vijay ; McMichael, John ; Lever, Jacqueline ; Burckart, Gilbert ; Starzl, Thomas. / Clinical Pharmacokinetics of Tacrolimus. In: Clinical Pharmacokinetics. 1995 ; Vol. 29, No. 6. pp. 404-430.
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Venkataramanan, R, Swaminathan, A, Prasad, T, Jain, A, Zuckerman, S, Warty, V, McMichael, J, Lever, J, Burckart, G & Starzl, T 1995, 'Clinical Pharmacokinetics of Tacrolimus', Clinical Pharmacokinetics, vol. 29, no. 6, pp. 404-430. https://doi.org/10.2165/00003088-199529060-00003

Clinical Pharmacokinetics of Tacrolimus. / Venkataramanan, Raman; Swaminathan, Arun; Prasad, Tata; Jain, Ashok; Zuckerman, Sheila; Warty, Vijay; McMichael, John; Lever, Jacqueline; Burckart, Gilbert; Starzl, Thomas.

In: Clinical Pharmacokinetics, Vol. 29, No. 6, 12.1995, p. 404-430.

Research output: Contribution to journalReview article

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AU - Venkataramanan, Raman

AU - Swaminathan, Arun

AU - Prasad, Tata

AU - Jain, Ashok

AU - Zuckerman, Sheila

AU - Warty, Vijay

AU - McMichael, John

AU - Lever, Jacqueline

AU - Burckart, Gilbert

AU - Starzl, Thomas

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N2 - Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and α1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.

AB - Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and α1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.

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Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V et al. Clinical Pharmacokinetics of Tacrolimus. Clinical Pharmacokinetics. 1995 Dec;29(6):404-430. https://doi.org/10.2165/00003088-199529060-00003