Skip to main content
SpringerLink
Log in

Physiological modelling of renal drug clearance

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

Summary

A physiological model of renal drug clearance is presented with the aim of establishing a basis for adjusting drug dosing regimens in renal insufficiency. In agreement with the morphology of blood supply to the nephron, the model assumes serial arrangement of the processes involved in drug excretion. Fractional extraction by filtration in the glomeruli is defined in terms of the product of the unbound fraction of the drug, the filtration fraction being responsible for the limited extraction efficiency of this process. For a description of the limitations of the tubular secretory process by plasma flow through peritubular capillaries, the parallel tube model is utilized. The assumption of direct proportionality between the transport maximum of the secretory process and filtrate flow in the tubules permits a quantitative comparison of the intrinsic tubular secretion clearance and the effectiveness of the filtration process. Provided that the secretory mechanism is highly effective, renal clearance becomes dependent only on kidney plasma flow and the fraction of drug not reabsorbed in the tubules. Tubular reabsorption results only in a proportional decrease in renal clearance.

The model predicts proportionality of renal drug clearance to GFR, which as a rule is used for dosage adjustment of drugs in renal insufficiency, only for compounds exclusively excreted by filtration. Compounds also excreted by tubular secretion in general exhibit a curvilinear relationship. The curvature is less pronounced as an increasing fraction of the drug is protein bound in blood. Therefore, for dosage adjustment of drugs secreted in the tubules and highly bound in blood, proportionality between renal clearance and GFR can serve as a reasonable approximation. According to the model, distinct deviations from simple proportionality, which will require dosage adjustment methods involving assessment both of glomerular and tubular functions of the kidney, can be expected mainly for drugs for which an efficient flow-dependent secretion process is not counteracted by extensive binding of the drug to blood constituents.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

C1 :

Drug concentration in the vicinity of transporting carrier molecules

CTSi :

Drug concentration flowing into the secretory segment of the peritubular capillary system

CTSo :

Drug concentration flowing out of the secretory segment of the peritubular capillary system

Cmax :

Maximal drug concentration that can appear in the filtrate

CLGF :

Clearance by filtration in the glomeruli

CLR :

Renal clearance

CLR(I):

Renal drug clearance at impaired kidney function

CLR(N):

Renal drug clearance at normal kidney function

CLuS, int :

Intrinsic tubular secretion clearance of unbound drug

GFR:

Glomerular filtration rate

EGF :

Filtration extraction ratio

ETS :

Secretion extraction ratio

FF :

Filtration fraction

FR :

Fraction of drug reabsorbed in the tubules

fe :

Fraction of drug excreted unchanged into urine

K′M :

Michaelis constant

KTS :

Tubular secretory efficiency compared to GFR

QPTS :

Plasma flow entering the peritubular capillary system

QR :

Renal plasma flow

Smax :

Secretion maximum

Tmax :

Transport maximum

References

  1. Dettli L, Spring P, Ryter S (1971) Multiple dose kinetics and drug dosage in patients with kidney disease. Acta Pharmacol (Kbh) 29 [Suppl 3]:211–224

    CAS  Google Scholar 

  2. Fabre J, Balant L (1976) Renal failure, drug pharmacokinetics and drug action. Clin Pharmacokinet 1:99–120

    PubMed  CAS  Google Scholar 

  3. Tucker GT (1981) Measurement of the renal clearance of drugs. Br J Clin Pharmacol 12:761–770

    PubMed  CAS  Google Scholar 

  4. Schück O, Nádvorníková H, Grafnetterová J, Reitschlägerová V (1985) Relationship between renal clearance of drugs and glomerular filtration rate in patients with chronic renal insufficiency. Int J Clin Pharmacol 23 [Suppl 1]:S42-S47

    Google Scholar 

  5. Turnheim K (1991) Pitfalls of pharmacokinetic dosage guidelines in renal insufficiency. Eur J Clin Pharmacol 40:87–93

    Article  PubMed  CAS  Google Scholar 

  6. Bricker NS, Klahr S, Lubowitz H, Rieselbach RE (1965) Renal function in chronic renal disease. Medicine 44:263–288

    PubMed  CAS  Google Scholar 

  7. Gloff CA, Benet LZ (1989) Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats. J Pharmacokinet Biopharm 17:169–177

    Article  PubMed  CAS  Google Scholar 

  8. Lin JH, Lin TH (1988) Renal handling of drugs in renal failure I. Differential effects of uranyl nitrate and glycerol-induced acute renal failure on renal excretion of TEAB and PAH in rats. J Pharmacol Exp Ther 246:896–901

    PubMed  CAS  Google Scholar 

  9. Orme BM, Cutler RE (1969) The relationship between kannamycin pharmacokinetics: distribution and renal function. Clin Pharmacol Ther 10:543–550

    PubMed  CAS  Google Scholar 

  10. Petitpierre B, Perrin L, Rudhardt M, Herrera A, Fabre J (1972) Behaviour of chlorpropamide in renal insufficiency and under the effect of associated drug therapy. Int J Clin Pharmacol Ther Toxicol 6:120–124

    CAS  Google Scholar 

  11. Hori R, Okumura K, Kamiya A, Nihira H, Nakano H (1983) Ampicillin and cephalexin in renal insufficiency. Clin Pharmacol Ther 34:792–798

    Article  PubMed  CAS  Google Scholar 

  12. Garrett ER (1978) Pharmacokinetics and clearances related to renal processes. Int J Clin Pharmacol 16:155–172

    CAS  Google Scholar 

  13. Levy G (1980) Effect of plasma protein binding on renal clearance of drugs. J Pharm Sci 69:482–483

    PubMed  CAS  Google Scholar 

  14. Duchin KL, Schrier RW (1978) Interrelationship between renal haemodynamics, drug kinetics and drug action. Clin Pharmacokinet 3:58–71

    PubMed  CAS  Google Scholar 

  15. Rowland M (1984) Protein binding and drug clearance. Clin Pharmacokinet 9 [Suppl 1]: 10–17

    PubMed  CAS  Google Scholar 

  16. Bass L, Keiding S (1988) Physiologically based models and strategic experiments in hepatic pharmacology. Biochem Pharmacol 37:1425–1431

    Article  PubMed  CAS  Google Scholar 

  17. Shannon JA (1939) Renal tubular excretion. Physiol Rev 19:63–93

    Google Scholar 

  18. Handley CA, Sigafoos RB, La Forge M (1949) Proportional changes in renal tubular reabsorption of dextrose and excretion of p-aminohippurate with changes in glomerular filtration. Am J Physiol 159:175–180

    PubMed  CAS  Google Scholar 

  19. Häberle D (1975) Influence of glomerular filtration rate on the rate of para-aminohippurate secretion by the rat kidney: Micropuncture and clearance studies. Kidney Int 7:385–396

    PubMed  Google Scholar 

  20. Deetjen P, Sonnenberg H (1965) Der tubuläre Transport von p-Aminohippursäure. Pflügers Archiv 285:25–44

    Article  Google Scholar 

  21. Häberle DA, Ruhland G, Lausser A, Moore L, Neiss A (1978) Influence of glomerular filtration rate on renal PAH secretion rate in the rat kidney. Pflügers Archiv 373:131–139

    Article  Google Scholar 

  22. Grantham JJ, Qualizza PB, Irwing R (1974) Net fluid secretion in proximal straight renal tubules in vitro: role of PAH. Am J Physiol 226:191–197

    PubMed  CAS  Google Scholar 

  23. Tozer TN (1974) Nomograms for modification of dosage regimens in patients with chronic renal function impairment. J Pharmacokinet Biopharm 2:13–28

    Article  Google Scholar 

  24. Chennavasin P, Craig Brater D (1981) Nomograms for drug use in renal disease. Clin Pharmacokinet 6:193–214

    PubMed  CAS  Google Scholar 

  25. Schück O (1987) Plasma protein binding of drugs and adjustment of their dosing regimen in patients with chronic renal failure. Int J Clin Pharmacol Ther Toxicol 25:476–478

    PubMed  Google Scholar 

  26. Bowman WC, Rand MJ, West GB (1968) Textbook of Pharmacology. Blackwell, Oxford Edinburgh, pp 334–356

    Google Scholar 

  27. Crone C, Levitt DG, Renkin EM, Michels CC (eds), In: Handbook of Physiology. The Cardiovascular System, vol. 4, American Physiological Society Bethesda, MD, pp 411–466

  28. Bowman RH (1975) Renal secretion of35S-furosemide and its depression by albumin binding. Am J Physiol 229:93–98

    PubMed  CAS  Google Scholar 

  29. Hall S, Rowland M (1985) Influence of fraction unbound upon renal clearance of furosemide in the isolated perfused rat kidney. J Pharmacol Exp Ther 218:122–127

    Google Scholar 

  30. Sjöström P, Odlind B, Beermann B, Hammarlund Udenaes M (1987) Changes of furosemide pharmacokinetics induced by dehydration. In: Andreucci VE, Dal Canton A (eds) Diuretics: basic pharmacological and clinical aspects. Martinus Nijhoff, Boston, USA, pp 107–109

    Google Scholar 

  31. Cutler RE, Blair AD (1979) Clinical pharmacokinetics of frusemide. Clin Pharmacokinet 4:279–286

    Article  PubMed  CAS  Google Scholar 

  32. Sjöström P, Odlind B, Beermann B, Karlberg B (1989) Pharmacokinetics and effects of frusemide in patients with nephrotic syndrome. Eur J Clin Pharmacol 37:173–180

    Article  PubMed  Google Scholar 

  33. Hori R, Sunayashiki K, Kamiya A (1976) Pharmacokinetic analysis of renal handling of sulfamethizole. J Pharm Sci 65:463–465

    PubMed  CAS  Google Scholar 

  34. Hori R, Okumura K, Nihira H, Nakano H, Akagi K, Kamiya A (1985) A new dosing regimen in renal insufficiency: application to cephalexin. Clin Pharmacol Ther: 290–295

Download references

Author information

Authors and Affiliations

  1. Institute of Pharmacology, Academy of Sciences of Czech Republic, Albertov 4, 12800, Prague, Czech Republic

    I. Janků

Authors
  1. I. Janků
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janků, I. Physiological modelling of renal drug clearance. Eur J Clin Pharmacol 44, 513–519 (1993). https://doi.org/10.1007/BF02440850

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02440850

Key words

Search

Navigation