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.
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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
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
Fabre J, Balant L (1976) Renal failure, drug pharmacokinetics and drug action. Clin Pharmacokinet 1:99–120
Tucker GT (1981) Measurement of the renal clearance of drugs. Br J Clin Pharmacol 12:761–770
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
Turnheim K (1991) Pitfalls of pharmacokinetic dosage guidelines in renal insufficiency. Eur J Clin Pharmacol 40:87–93
Bricker NS, Klahr S, Lubowitz H, Rieselbach RE (1965) Renal function in chronic renal disease. Medicine 44:263–288
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
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
Orme BM, Cutler RE (1969) The relationship between kannamycin pharmacokinetics: distribution and renal function. Clin Pharmacol Ther 10:543–550
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
Hori R, Okumura K, Kamiya A, Nihira H, Nakano H (1983) Ampicillin and cephalexin in renal insufficiency. Clin Pharmacol Ther 34:792–798
Garrett ER (1978) Pharmacokinetics and clearances related to renal processes. Int J Clin Pharmacol 16:155–172
Levy G (1980) Effect of plasma protein binding on renal clearance of drugs. J Pharm Sci 69:482–483
Duchin KL, Schrier RW (1978) Interrelationship between renal haemodynamics, drug kinetics and drug action. Clin Pharmacokinet 3:58–71
Rowland M (1984) Protein binding and drug clearance. Clin Pharmacokinet 9 [Suppl 1]: 10–17
Bass L, Keiding S (1988) Physiologically based models and strategic experiments in hepatic pharmacology. Biochem Pharmacol 37:1425–1431
Shannon JA (1939) Renal tubular excretion. Physiol Rev 19:63–93
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
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
Deetjen P, Sonnenberg H (1965) Der tubuläre Transport von p-Aminohippursäure. Pflügers Archiv 285:25–44
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
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
Tozer TN (1974) Nomograms for modification of dosage regimens in patients with chronic renal function impairment. J Pharmacokinet Biopharm 2:13–28
Chennavasin P, Craig Brater D (1981) Nomograms for drug use in renal disease. Clin Pharmacokinet 6:193–214
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
Bowman WC, Rand MJ, West GB (1968) Textbook of Pharmacology. Blackwell, Oxford Edinburgh, pp 334–356
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
Bowman RH (1975) Renal secretion of35S-furosemide and its depression by albumin binding. Am J Physiol 229:93–98
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
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
Cutler RE, Blair AD (1979) Clinical pharmacokinetics of frusemide. Clin Pharmacokinet 4:279–286
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
Hori R, Sunayashiki K, Kamiya A (1976) Pharmacokinetic analysis of renal handling of sulfamethizole. J Pharm Sci 65:463–465
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
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Janků, I. Physiological modelling of renal drug clearance. Eur J Clin Pharmacol 44, 513–519 (1993). https://doi.org/10.1007/BF02440850
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DOI: https://doi.org/10.1007/BF02440850