Chapter 16 Routes of Excretion

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Renal Disease Considerations

Getting back to the renal excretion of drugs. If a drug is extensively excreted unchanged into urine (i.e. fe closer to 1), alteration of renal function will extensively alter the drug elimination rate. Fortunately creatinine or inulin clearance can be used as a measure of renal function. For most drugs which are excreted extensively as unchanged drug it has been found that there is a good correlation between creatinine or inulin clearance and drug clearance or observed renal clearance and elimination rate (since V is usually unchanged).

Dose adjustment

Creatinine clearance

Creatinine is produced in the body by muscle metabolism from creatine phosphate. Creatinine production is dependent on the age, weight, and sex of the patient. Elimination of creatinine is mainly by glomerular filtration (> 90%) with a small percentage by active secretion. With the patient in stable condition the production is like a continuous infusion to steady state with the infusion rate controlled by muscle metabolism and the elimination controlled by renal function. Thus as renal function is reduced serum creatinine concentrations increases. Other compounds such as inulin are also used for GFR measurement. Although inulin GFR values are probably more accurate they involve administration of inulin and careful collection of urine for inulin determination. The major advantage of creatinine is that its formation is endogenous. Determination of creatinine clearance consists of collection of total urine and a plasma/serum determination at the mid-point time. Thus:

Equation 16.7.1 Creatinine Clearance

with serum creatinine expressed as mg/100 ml and creatinine clearance as ml/min. Normal inulin clearance values are 124 ml/min for men and 109 ml/min for women (Documenta Geigy, 1970). Because of some small renal secretion of creatinine, normal values of creatinine clearance are slightly higher than GFR measured with inulin. Thus, normal creatinine clearance values are about 120 to 130 ml/min.

Various investigators have developed equations which allow calculation of creatinine clearance using serum creatinine values. Thus a single serum level may used when renal condition is stable. One commonly used equation is that of Cockcroft and Gault.

Males:

Equation 16.7.2 Creatinine Clearance

Females: Use 85% of the value calculated for males. Cs_Cr is the serum creatinine concentration in mg/dl. The original authors of this equation used actual body weight in Equation 16.7.2. More recently it has been recommended that ideal body (IBW) be used in this equation unless the actual body weight (ABW) is less (Murphy, 2001). This is consistent with earlier the recommendation to use lean body weight in Equation 16.7.2 as creatinine is formed in muscle (Shargel and Yu, 1985).

Equation 16.7.3 Ideal Body weight (Murphy, 2001, p4-5)

More recent equations for estimating creatinine clearance are those recommended by the National Kidney Disease Education Program (NKDEP) for adults (from the MDRD study) and children (Original Schwartz equation) calculation.

Estimation of kel in a patient

The relationship between creatinine clearance and overall drug elimination can be easily seen by looking at plots of kel observed versus creatinine clearance.

Figure 16.7.1 Plot of kel versus CLCR (Dettli Plot)

These are often called Dettli plots.

Figure 16.7.1 shows the situation with considerable excretion as unchanged drug. i.e. fe between 0.3 and 0.7.

Figure 16.7.2 Dettli Plot (fe = 1)

In Figure 16.7.2 drug is excreted entirely as unchanged drug. i.e. fe = 1

Figure 16.7.3 Dettli Plot (fe = 0)

In Figure 16.7.3 drug is excretion only as metabolized drug. i.e. fe = 0

We can use this information to calculate initial dosage regimens for patients taking drugs with high (> 0.25) fe values. The first step is to estimate the creatinine clearance in the patient from their serum creatinine value. From a Dettli plot (kel versus CLcr) constructed from previous studies with this drug we can estimate the elimination rate constant in this patient. We can therefore calculate an optimum dose and dosing interval to achieve the desired average drug concentration or maximum or minimum drug concentrations. The Dettli plot may be built into a computer program or nomogram.

Figure 16.7.4 Dettli Plot Showing kel Observed versus CL_cr

This is the plot shown before. In the references shown below there is information useful for calculating kel in patients with impaired renal function.

Table 16.7.1 Some Example Values (Wagner, 1975)

knr b

Kanamycin 0.01 0.0024

Sulfadiazine 0.03 0.0005

Tetracycline 0.008 0.00072

As an example these data could be used to calculate the kel for a patient with a CLcr of 10 ml/min compared a subject with normal renal function of 120 ml/min

For kanamycin

kel_patient = knr + b • CLcr = 0.01 + 0.0024 x 10 = 0.01 + 0.024 = 0.034 hr^-1

Compare this with the value for the normal subject: kel = 0.01 + 0.0024 x 120 = 0.298 hr^-1

For sulfadiazine

kel_patient = 0.03 + 0.0005 x 10 = 0.03 + 0.005 = 0.035 hr^-1

Compare this with the value for the normal subject: kel = 0.03 + 0.0005 x 120 = 0.09 hr^-1

For tetracycline

kel_patient = 0.008 + 0.00072 x 10 = 0.008 + 0.0072 = 0.0152 hr^-1

Compare this with the value for the normal subject: kel = 0.008 + 0.00072 x 120 = 0.0944 hr^-1

References

Documenta Geigy, Scientific Tables. 7th ed., Geigy Pharmaceuticals, 1970, p531
Shargel, L. and Yu, A.B.C. 1985 Applied Biopharmaceutics and Pharmacokinetics, 2nd ed., Appleton-Century-Crofts, Norwalk, CT, page 312
Murphy, J.E. 2001 Clinical Pharmacokinetics, 2nd ed., ASHP, Bethesda, MD
Wagner, J.G. 1975 Fundamentals of Clinical Pharmacokinetics, Drug Intelligence Publications, Inc., Hamilton, IL
Dettli, L.C. 1974 Drug dosage in patients with renal disease, Clin. Pcol. Therap., 16, 274-80
Chow, J. Clin. P'col. 15, 405 (1975)
Welling, Clin. P'col. 18, 45 (1975)
Bennett, Annals Int.Med. 754 (1977)

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	knr	b
Kanamycin	0.01	0.0024
Sulfadiazine	0.03	0.0005
Tetracycline	0.008	0.00072