Abstract
Purpose
Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Clcrea).
Methods
The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin.
Results
The diabetic patients revealed of a wide range of age (32–88 years), BMI values (19.8–54.7 kg/m2), and extent of polypharmacotherapy (1–21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients’ Clcrea ranged from 21.6–155.9 mL/min. The results indicated statistically significant correlations (p < 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23–4.99 μg/mL. The estimated elimination half-life (t ½) of metformin was 11.9 h in patients with a ClCrea higher than 60 mL/min and 18.5 h for diabetics with lower ClCrea. Sitagliptin capillary blood concentrations ranged between 11.12–995.6 ng/mL. Calculated t ½ of sitagliptin were 8.4 h and 13.0 h in patients with a ClCrea above and below 60 mL/min, respectively.
Conclusions
DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.
Similar content being viewed by others
References
Enderle Y, Foerster K, Burhenne J (2016) Clinical feasibility of dried blood spots: analytics, validation, and applications. J Pharm Biomed Anal 130:231–243. https://doi.org/10.1016/j.jpba.2016.06.026
Wilhelm AJ, den Burger JC, Swart EL (2014) Therapeutic drug monitoring by dried blood spot: progress to date and future directions. Clin Pharmacokinet 53(11):961–973. https://doi.org/10.1007/s40262-014-0177-7
Martial LC, Aarnoutse RE, Schreuder MF, Henriet SS, Bruggemann RJ, Joore MA (2016) Cost evaluation of dried blood spot home sampling as compared to conventional sampling for therapeutic drug monitoring in children. PLoS One 11(12):e0167433. https://doi.org/10.1371/journal.pone.0167433
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41
Drenth-van Maanen AC, Jansen PA, Proost JH, Egberts TC, van Zuilen AD, van der Stap D, van Marum RJ (2013) Renal function assessment in older adults. Br J Clin Pharmacol 76(4):616–623. https://doi.org/10.1111/bcp.12199
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50(2):81–98. https://doi.org/10.2165/11534750-000000000-00000
Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK (2014) Metformin in patients with type 2 diabetes and kidney disease: a systematic review. Jama 312(24):2668–2675. https://doi.org/10.1001/jama.2014.15298
DeFronzo R, Fleming GA, Chen K, Bicsak TA (2016) Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism 65(2):20–29. https://doi.org/10.1016/j.metabol.2015.10.014
Lalau JD, Lacroix C (2003) Measurement of metformin concentration in erythrocytes: clinical implications. Diabetes Obes Metab 5(2):93–98
Lalau JD, Lemaire-Hurtel AS, Lacroix C (2011) Establishment of a database of metformin plasma concentrations and erythrocyte levels in normal and emergency situations. Clin Drug Investig 31(6):435–438
Scheen AJ (2010) Pharmacokinetic and pharmacodynamic evaluation of sitagliptin plus metformin. Expert Opin Drug Metab Toxicol 6(10):1265–1276. https://doi.org/10.1517/17425255.2010.513699
Scherf-Clavel M, Högger P (2015) Analysis of metformin, sitagliptin and creatinine in human dried blood spots. J Chromatogr B Anal Technol Biomed Life Sci 997:218–228. https://doi.org/10.1016/j.jchromb.2015.06.014
Scheen AJ (1996) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30(5):359–371
Piccoli GB, Grassi G, Cabiddu G, Nazha M, Roggero S, Capizzi I, De Pascale A, Priola AM, Di Vico C, Maxia S, Loi V, Asunis AM, Pani A, Veltri A (2015) Diabetic kidney disease: a syndrome rather than a single disease. Rev Diabet Stud 12(1–2):87–109. https://doi.org/10.1900/RDS.2015.12.87
Pazhayattil GS, Shirali AC (2014) Drug-induced impairment of renal function. Int J Nephrol Renov Dis 7:457–468. https://doi.org/10.2147/IJNRD.S39747
Loboz KK, Shenfield GM (2005) Drug combinations and impaired renal function -- the 'triple whammy'. Br J Clin Pharmacol 59(2):239–243. https://doi.org/10.1111/j.0306-5251.2004.2188.x
Onuigbo MA (2013) The nephrotoxic "triple whammy" of combining diuretics, ACE inhibitors, and NSAIDs. BMJ 346:f678. https://doi.org/10.1136/bmj.f678
Prieto-Garcia L, Pericacho M, Sancho-Martinez SM, Sanchez A, Martinez-Salgado C, Lopez-Novoa JM, Lopez-Hernandez FJ (2016) Mechanisms of triple whammy acute kidney injury. Pharmacol Ther 167:132–145. https://doi.org/10.1016/j.pharmthera.2016.07.011
Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S (2013) Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 346:e8525. https://doi.org/10.1136/bmj.e8525
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130(6):461–470
den Burger JC, Wilhelm AJ, Chahbouni AC, Vos RM, Sinjewel A, Swart EL (2015) Haematocrit corrected analysis of creatinine in dried blood spots through potassium measurement. Anal Bioanal Chem 407(2):621–627. https://doi.org/10.1007/s00216-014-8291-9
Koop DR, Bleyle LA, Munar M, Cherala G, Al-Uzri A (2013) Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 926:54–61
Keevil BG (2011) The analysis of dried blood spot samples using liquid chromatography tandem mass spectrometry. Clin Biochem 44(1):110–118
Koster RA, Greijdanus B, Alffenaar JW, Touw DJ (2015) Dried blood spot analysis of creatinine with LC-MS/MS in addition to immunosuppressants analysis. Anal Bioanal Chem 407(6):1585–1594. https://doi.org/10.1007/s00216-014-8415-2
Cohen E, Nardi Y, Krause I, Goldberg E, Milo G, Garty M, Krause I (2014) A longitudinal assessment of the natural rate of decline in renal function with age. J Nephrol 27(6):635–641. https://doi.org/10.1007/s40620-014-0077-9
Bardin C, Nobecourt E, Larger E, Chast F, Treluyer JM, Urien S (2012) Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus. Eur J Clin Pharmacol 68(6):961–968
Duong JK, Kroonen M, Kumar SS, Heerspink HL, Kirkpatrick CM, Graham GG, Williams KM, Day RO (2017) A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function. Eur J Clin Pharmacol 73(8):981–990. https://doi.org/10.1007/s00228-017-2251-1
Dissanayake AM, Wheldon MC, Hood CJ (2018) Pharmacokinetics of metformin in patients with chronic kidney disease stage 4 and metformin-naive type 2 diabetes. Pharmacol Res Perspect 6(5):e00424. https://doi.org/10.1002/prp2.424
Chen X, Zhao Q, Zhang J, Liu T, Jiang J, Hu P (2016) An open-label, multiple-dose study to assess the pharmacokinetics and tolerability of sitagliptin/metformin fixed-dose combination (FDC) tablet in healthy Chinese adult subjects. Int J Clin Pharmacol Ther 54(9):705–711. https://doi.org/10.5414/CP202646
Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA (2006) Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 28(1):55–72. https://doi.org/10.1016/j.clinthera.2006.01.015
Radley A, Melville K, Tait J, Stephens B, Evans JMM, Dillon JF (2017) A quasi-experimental evaluation of dried blood spot testing through community pharmacies in the Tayside region of Scotland. Frontline Gastroenterol 8(3):221–228. https://doi.org/10.1136/flgastro-2016-100776
Acknowledgements
The authors would like to thank the patients and all 14 engaged community pharmacies for their participation in this study. The excellent technical assistance of Sabrina Rösel (office of Drs. Albert and Zieher) is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Patients were recruited and enrolled in the study after written informed consent. The study was approved by the ethics committee of the Medical Faculty of the University of Würzburg (reference number 287/14) and the Freiburg Ethics Committee International (FEKI) and registered by ISRCTN (ISRCTN14518136).
Conflict of interests
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Figure S1
(DOCX 283 kb)
Rights and permissions
About this article
Cite this article
Scherf-Clavel, M., Albert, E., Zieher, S. et al. Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study. Eur J Clin Pharmacol 75, 809–816 (2019). https://doi.org/10.1007/s00228-019-02637-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-019-02637-w