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Tacrolimus Concentration in Saliva of Kidney Transplant Recipients: Factors Influencing the Relationship with Whole Blood Concentrations

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Abstract

Objective

The objective of this study was to examine the association between tacrolimus concentration in oral fluids and in whole blood and to investigate the various factors that influence this relationship.

Patients and Methods

Forty-six adult kidney transplant recipients were included in the study. Study A (ten patients) included the collection of several paired oral fluid samples by passive drool over a 12-h post-dose period. Study B (36 patients) included the collection of oral fluids pre-dose and at 2 h after the tacrolimus dose under three conditions: un-stimulated, after stimulation with a tart candy, and after mouth rinsing. The tacrolimus concentration in oral fluids was measured by a specially developed sensitive and specific liquid chromatography mass spectrometry method. A salivary transferrin concentration of >1 mg/dL was used as a cut-off value for oral fluid blood contamination.

Results

Rinsing the oral cavity before sampling proved to provide the most suitable sampling strategy giving a correlation coefficient value of 0.71 (p = 0.001) between the tacrolimus concentration in oral fluids and the tacrolimus concentration in whole blood at trough. Mean and 95% confidence interval of tacrolimus concentration in oral fluids at the pre-dose concentration for samples collected after mouth rinsing was 584 (436, 782) pg/mL. The ratio of the tacrolimus concentration in oral fluids to the tacrolimus concentration in whole blood (*100) was 11% (95% confidence interval 9–13) for all sampling times. Oral fluid pH or weight of a saliva sample did not influence the tacrolimus concentration in oral fluids. Tacrolimus distribution into oral fluids exhibited a delay with a pronounced counter-clockwise hysteresis with respect to the time after dose. A multivariate analysis of variance revealed that the tacrolimus concentration in oral fluids is related to the tacrolimus concentration in whole blood and tacrolimus plasma-binding proteins including albumin and cholesterol.

Conclusion

An optimal sampling strategy for the determination of the tacrolimus concentration in oral fluids was established. Measuring the tacrolimus concentration in oral fluids appears to be a feasible and non-invasive method for predicting the concentration of tacrolimus in whole blood.

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Abbreviations

AUC:

Area under the concentration-time curve

BCRP:

Breast cancer resistance protein (BCRP), encoded by the ABCG2 gene

BSEP:

Bile salt export pump (BSEP), encoded by the ABCB11 gene

C0:

Tacrolimus concentration before dose

C2:

Tacrolimus concentration at 2 h after dose

C max :

Maximum concentration

CV:

Coefficient of variation

CYP:

Cytochrome P450

LLOQ:

Lower limit of quantification

MRP2:

Multidrug resistance-associated protein 2 (MRP2), encoded by the ABCC2 gene

OF:

Oral fluids

P-gp:

Permeability glycoprotein or multidrug resistance protein 1 (MDR1) encoded by the ABCB1 gene

TAC:

Tacrolimus

TAC-OF:

Tacrolimus concentration in oral fluid

TAC-WB:

Tacrolimus concentration in whole blood

TRNs:

Transferrin concentration in saliva

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Acknowledgements

The authors sincerely thank Ms. Maria Medeiros, RN, for her help in conducting the clinical studies and Dr. Ken Ogasawara for genotyping the patients.

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Authors and Affiliations

  1. Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 495A College of Pharmacy, 7 Greenhouse Road, Kingston, RI, 02881, USA

    Mwlod Ghareeb & Fatemeh Akhlaghi

  2. Division of Organ Transplantation, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Reginald Y. Gohh

Authors
  1. Mwlod Ghareeb
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  2. Reginald Y. Gohh
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  3. Fatemeh Akhlaghi
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Correspondence to Fatemeh Akhlaghi.

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Funding

This study was funded by the Rhode Island Science and Technology Advisory Council and the University of Rhode Island, College of Pharmacy.

Conflict of interest

Mwlod Ghareeb, Reginald Y. Gohh, and Fatemeh Akhlaghi have no conflicts of interest directly relevant to the content of this article.

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Ghareeb, M., Gohh, R.Y. & Akhlaghi, F. Tacrolimus Concentration in Saliva of Kidney Transplant Recipients: Factors Influencing the Relationship with Whole Blood Concentrations. Clin Pharmacokinet 57, 1199–1210 (2018). https://doi.org/10.1007/s40262-017-0626-1

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