Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model

Alan B. Watts, Adam M. Cline, Adham R. Saad, Scott B Johnson, Jay I Peters, Robert O. Williams

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Lung transplantation animal models have been well established and enabled the investigation of a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. Direct administration of immunosuppressive agents to the lung is a commonly investigated approach; however, can prove challenging due to the poor solubility of the drug molecule, the tortuous pathways of the lung periphery, and the limited number of excipients approved for inhalation. In this study, we aimed to evaluate a solubility enhancing formulation of tacrolimus for localized therapy in a lung transplanted rat model and determine the extent of drug absorption into systemic circulation. Characterization of the nebulized tacrolimus dispersion for nebulization showed a fine particle fraction (FPF) of 46.1% and a mass median aerodynamic diameter (MMAD) of 4.06 μm. After single dose administration to transplanted and non-transplanted rats, a mean peak transplanted lung concentration of 399.8 ± 29.2 ng/g and mean peak blood concentration of 4.88 ± 1.6 ng/mL were achieved. It is theorized that enhanced lung retention of tacrolimus is due to lipophilic associations with bronchial tissue and phospholipid surfactants in lung fluid. These findings indicate that tacrolimus dispersion for nebulization can achieve highly localized therapy for lung transplant recipients.

Original languageEnglish (US)
Pages (from-to)46-52
Number of pages7
JournalInternational Journal of Pharmaceutics
Volume384
Issue number1-2
DOIs
StatePublished - Jan 15 2010

Fingerprint

Tacrolimus
Rodentia
Pharmacokinetics
Lung
Solubility
Lung Transplantation
Excipients
Immunosuppressive Agents
Surface-Active Agents
Pharmaceutical Preparations
Inhalation
Allografts
Phospholipids
Animal Models
Therapeutics

Keywords

  • Lung transplant
  • Nanoparticles
  • Preclinical
  • Pulmonary delivery
  • Tacrolimus

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model. / Watts, Alan B.; Cline, Adam M.; Saad, Adham R.; Johnson, Scott B; Peters, Jay I; Williams, Robert O.

In: International Journal of Pharmaceutics, Vol. 384, No. 1-2, 15.01.2010, p. 46-52.

Research output: Contribution to journalArticle

@article{153c7fc6667d4d59a39bacd3d08e0d87,
title = "Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model",
abstract = "Lung transplantation animal models have been well established and enabled the investigation of a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. Direct administration of immunosuppressive agents to the lung is a commonly investigated approach; however, can prove challenging due to the poor solubility of the drug molecule, the tortuous pathways of the lung periphery, and the limited number of excipients approved for inhalation. In this study, we aimed to evaluate a solubility enhancing formulation of tacrolimus for localized therapy in a lung transplanted rat model and determine the extent of drug absorption into systemic circulation. Characterization of the nebulized tacrolimus dispersion for nebulization showed a fine particle fraction (FPF) of 46.1{\%} and a mass median aerodynamic diameter (MMAD) of 4.06 μm. After single dose administration to transplanted and non-transplanted rats, a mean peak transplanted lung concentration of 399.8 ± 29.2 ng/g and mean peak blood concentration of 4.88 ± 1.6 ng/mL were achieved. It is theorized that enhanced lung retention of tacrolimus is due to lipophilic associations with bronchial tissue and phospholipid surfactants in lung fluid. These findings indicate that tacrolimus dispersion for nebulization can achieve highly localized therapy for lung transplant recipients.",
keywords = "Lung transplant, Nanoparticles, Preclinical, Pulmonary delivery, Tacrolimus",
author = "Watts, {Alan B.} and Cline, {Adam M.} and Saad, {Adham R.} and Johnson, {Scott B} and Peters, {Jay I} and Williams, {Robert O.}",
year = "2010",
month = "1",
day = "15",
doi = "10.1016/j.ijpharm.2009.09.040",
language = "English (US)",
volume = "384",
pages = "46--52",
journal = "International Journal of Pharmaceutics",
issn = "0378-5173",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model

AU - Watts, Alan B.

AU - Cline, Adam M.

AU - Saad, Adham R.

AU - Johnson, Scott B

AU - Peters, Jay I

AU - Williams, Robert O.

PY - 2010/1/15

Y1 - 2010/1/15

N2 - Lung transplantation animal models have been well established and enabled the investigation of a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. Direct administration of immunosuppressive agents to the lung is a commonly investigated approach; however, can prove challenging due to the poor solubility of the drug molecule, the tortuous pathways of the lung periphery, and the limited number of excipients approved for inhalation. In this study, we aimed to evaluate a solubility enhancing formulation of tacrolimus for localized therapy in a lung transplanted rat model and determine the extent of drug absorption into systemic circulation. Characterization of the nebulized tacrolimus dispersion for nebulization showed a fine particle fraction (FPF) of 46.1% and a mass median aerodynamic diameter (MMAD) of 4.06 μm. After single dose administration to transplanted and non-transplanted rats, a mean peak transplanted lung concentration of 399.8 ± 29.2 ng/g and mean peak blood concentration of 4.88 ± 1.6 ng/mL were achieved. It is theorized that enhanced lung retention of tacrolimus is due to lipophilic associations with bronchial tissue and phospholipid surfactants in lung fluid. These findings indicate that tacrolimus dispersion for nebulization can achieve highly localized therapy for lung transplant recipients.

AB - Lung transplantation animal models have been well established and enabled the investigation of a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. Direct administration of immunosuppressive agents to the lung is a commonly investigated approach; however, can prove challenging due to the poor solubility of the drug molecule, the tortuous pathways of the lung periphery, and the limited number of excipients approved for inhalation. In this study, we aimed to evaluate a solubility enhancing formulation of tacrolimus for localized therapy in a lung transplanted rat model and determine the extent of drug absorption into systemic circulation. Characterization of the nebulized tacrolimus dispersion for nebulization showed a fine particle fraction (FPF) of 46.1% and a mass median aerodynamic diameter (MMAD) of 4.06 μm. After single dose administration to transplanted and non-transplanted rats, a mean peak transplanted lung concentration of 399.8 ± 29.2 ng/g and mean peak blood concentration of 4.88 ± 1.6 ng/mL were achieved. It is theorized that enhanced lung retention of tacrolimus is due to lipophilic associations with bronchial tissue and phospholipid surfactants in lung fluid. These findings indicate that tacrolimus dispersion for nebulization can achieve highly localized therapy for lung transplant recipients.

KW - Lung transplant

KW - Nanoparticles

KW - Preclinical

KW - Pulmonary delivery

KW - Tacrolimus

UR - http://www.scopus.com/inward/record.url?scp=70649091111&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70649091111&partnerID=8YFLogxK

U2 - 10.1016/j.ijpharm.2009.09.040

DO - 10.1016/j.ijpharm.2009.09.040

M3 - Article

C2 - 19782740

AN - SCOPUS:70649091111

VL - 384

SP - 46

EP - 52

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1-2

ER -