Skip to main content
Log in

Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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

    Article  CAS  PubMed  Google Scholar 

  2. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. Lalau JD, Lacroix C (2003) Measurement of metformin concentration in erythrocytes: clinical implications. Diabetes Obes Metab 5(2):93–98

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  Google Scholar 

  13. Scheen AJ (1996) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30(5):359–371

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  Google Scholar 

  16. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Onuigbo MA (2013) The nephrotoxic "triple whammy" of combining diuretics, ACE inhibitors, and NSAIDs. BMJ 346:f678. https://doi.org/10.1136/bmj.f678

    Article  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  Google Scholar 

  22. 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

    Article  CAS  Google Scholar 

  23. Keevil BG (2011) The analysis of dried blood spot samples using liquid chromatography tandem mass spectrometry. Clin Biochem 44(1):110–118

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to Petra Högger.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-019-02637-w

Keywords

Navigation