Journal of Clinical and Hospital Pharmacy (1985) 10,337-349.

FACTORS CONTRIBUTING TO VARIABILITY IN DRUG PHARMACOKINETICS. IV. RENAL EXCRETION

Carl G. RegPrdh Department of Phamtacokinetics and Drug Metabolism, Hassle Research Laboratories, S-431 83, Molndal,

Sweden

S U M M A R Y

The renal excretion of drugs is mainly controlled by three factors: glomerular filtration, tubular secretion and tubular reabsorption. Only relatively polar drugs are excreted in appreciable amounts by the kidneys. Factors affecting renal excretion of drugs include: kidney function, protein binding, urine pH and urine flow. Impaired renal function may lead to a clinically significant accumulation of drugs eliminated by the kidneys, if more than 50°, of the dose is nurmally excreted unchanged in the urine and the renal function is less than SOO/b of the normal value. Successful removal of a drug by dialysis requires that it possesses a polar character, low protein binding and a small to moderate volume of distribution.

I N T R O D U C T I O N

The majority of drugs reach their site of action via the systemic circulation. The blood transports drug molecules to specific receptors localized, for instance, in the brain, the heart and the kidneys. However, a drug is rarely confined to a single type of tissue but instead is distributed to a multitude of different tissues though with some degree of selectivity. In drug therapy, most tissues mainly serve as reservoirs and only a few of them, primarily the liver and the kidneys, are capable of eliminating drugs from the body.

The elimination consists of biotransformation and excretion of the unchanged drug. The latter, predominantly takes place in the kidneys but the bile may also contribute significantly to the excretion of some specific drugs, although the contribution of biliary excretion to the overall elimination process is generally more pronounced in animals than in man.

Correspondence: Dr C. G. R e g k d h . Series edited by Dr D. Jack, Department of Clinical Pharmacology and Therapeutics, University of

Birmingham, U.K.

337

338 C . G . Regdrdh

A factor of major importance in determining whether a drug will be eliminated by metabolism or by renal excretion is water solubility. Very lipophilic drugs are trapped by the liver and metabolized by enzymes. Molecules which reach the kidneys are reabsorbed in the distal part of the tubules. On the other hand, very water soluble drugs are often not metabolized, and a major fraction of the dose is eliminated in unchanged form via the kidneys. Between these two extremes there is an infinite gradation of hepatic and renal influence on the overall elimination process.

The elimination of drugs by biotransformation was recently reviewed in this journal (1). The aim of the present paper is to give a brief survey of our present knowledge of renal excretion of drugs.

T R A N S P O R T M E C H A N I S M S The kidneys receive about 25:, of cardiac output which means that they are normally perfused by 1.2-1.5 litres of blood per minute. The blood supply provides the kidneys with nutrients and delivers endogenous and exogenous compounds which the body needs to eliminate. The primary anatomic unit of the kidney is the nephron. Each nephron is made up of the following anatomically distinguishable components: glomerulus, proximal tubule, loop of Henle, distal tubule and collecting duct (Fig. 1). The blood from the renal artery reaches the glomerulus first. It then perfuses the tubule via a network of interconnecting capillaries. The proximal part of the tubule receives the blood supply of the glomerulus but as the distance increases, from the glomerulus, more and more of the blood is diverted to the venous return and only a minor fraction of the initial blood volume to the nephron reaches the terminal end of the distal tubule and the collecting duct.

In the kidney, three major processes control the excretion of drugs, namely: glomerular filtration, active tubular secretion and passive tubular reabsorption. A fourth process-active tubular reabsorption-appears to play a minor role in drug excretion (2) and is therefore ignored in this context. The net result of these processes is defined as the renal clearance which has the dimension volume per time unit, for instance, ml/min or litre/h.

Renal clearance per se gives limited information about how the drug is handled by the kidney but if the clearance value substantially exceeds maximal glomerular filtra- tion rate (GFR), which is about l/Sth of the renal plasma flow, this is an indication that active tubular secretion is involved in the excretory process. On the contrary, a clearance value close to, or below, GFR does not exclude tubules secretion, since the effect of this mechanism might well be neutralized by reabsorption in the distal part of the tubule. Therefore, to study the different excretion mechanism of the kidney, compounds with specific renal excretion characteristics have to be used.

Glomerular filtration Of the volume of blood perfused through the kidneys, approximately l/5th of the

plasma water is normally filtered through the glomeruli by the hydrostatic pressure gradient between the glomerular capillaries and the adjacent part of the proximal tubules and the osmotic pressure, in the glomerular capillaries. The pores in the membrane of these capillaries are too narrow to alhw passage of macromolecules into the primary urine and hence, only the unbound drug fraction in the plasma is filtered in the glomeruli. The filtration rate of drugs in the kidneys is thus given by:

Drug pharmacokinerics I V . Renal excretion

-BASIC URINE

339

-ACIDIC URINE

NEPHRON UNIT

PART

DISTAL

TUBULE TUBULE CAPSULE CONVOLUTED CONVOLUTED

COLLECTIN( DUCT

RlNE

IXCRETION

Filtration rate = GFR x fu

wheref, is the free fraction of drug in the plasma. GFR is assessed by the use of several exogenous substances claimed to be specifi-

cally excreted by filtration in the glomeruli. Among these substances, inulin has been proved to give a corret estimate of GFR in animal experiments (3). The way inulin clearance is determined-infusion of the polysaccharide to a plateau level in the blood-makes the method too time consuming. Therefore, this method rarely seems to be the first alternative for GFR measurements.

T h e most common method for the assessment of GFR is instead based on the excretion of endogenous creatinine in the urine. However, according to most investi- gators this method overestimates GFR in individuals with high serum creatinine concentrations, i.e., those with impaired renal function. This is due to an increasing contribution of tubular secretion to the renal excretion of creatinine, with increasing creatinine concentrations in the plasma (4).

3 40 C . G. Regdrdh

A third, and relatively new, method for determination of GFR uses the dis- appearance rate of intravenously administered "Cr-EDTA from the plasma. This metal chelate is solely eliminated by glomerular filtration and the clearance of this sub- stance is highly correlated with the inulin clearance (5, 6 ) . The method is fast, needs no urine collection, and is therefore convenient for the patient. It requires, however, that the area under the plasma concentration time curve, AUC, is determined with sufficient accuracy, whereafter GFR is derived by dividing the dose by the AUC and multiplying by the correction factor 1.10 (7).

Despite the simplicity of the chromium chelate method it is still too complicated for routine application in the clinic. In this case, a single determination of serum creatinine is commonly used as an estimate of kidney function. By means of various nomograms, taking into consideration weight and age of the patient, creatinine clearance can be determined with reasonable accuracy (8,9).

Tubular secretion Drugs may also enter the urine by secretion from the blood into the fluid in the

tubular lumen. This process transports drug molecules against the concentration gradient-so-called active transport-and requires an energy supply in order that it may function.

The tubular secretion of drugs does not seem to be limited b y binding to plasma proteins since extensively bound drugs for example, indomethacin, naproxen and thiazides are eliminated by this mechanism. The tubular secretion seems to be promoted by at least two different transport mechanisms.

One of these mechanisms carries acidic drug molecules (anions) from the post- glomerular arterial blood into the tubular lumen. The other mechanism is associated with the secretion of basic compounds (cations) (10). Neither of these processes seems to be fully understood though the transport system of organic acids seems to better characterized (1 1).

The maximum rate at which a drug can be eliminated by tubular secretion is identi- cal to the renal blood flow. This requires, however, that all the drug in the renal arterial blood is removed, including those drug molecules bound to plasma proteins and those located in the erythrocytes. It also requires that the drug concentration in blood is far below that needed to saturate the active transport mechanism. Para- aminohippuric acid (PAH) fulfills these criteria but since this exogenous organic acid is located almost exclusively in the plasma, and is not reabsorbed in the distal tubule, the renal clearance of PAH is a measure of the renal plasma flow and correction for the haematocrit (H) has to be made to obtain the renal blood flow. (Renal blood flow = PAH clearance/( 1-H)). Some substances, for instance mecamylamine and prenalterol, have renal clearance values exceeding those of renal plarnsa flow (1 2, 13) this suggests that drug molecules located on or in the red blood cells are also extracted during the passage of blood through the active transport region.

Drugs which have renal clearance values that approach those of renal plasma flow or renal blood flow are, however, relatively rare. On the other hand, there are a great number of drugs, anions as well as cations, with renal clearance values that exceed maximum GFR and which are indicative of active tubular secretion. Table 1 shows some anionic and cationic drugs which have been found to be actively secreted by the kidney. Among these compounds, the acids have been found to interact competitively

Drug pharmacokinetics ZV. Renal excretion 34 1

with the excretion of each other. The most well-known interaction of this kind seems to be the effect of probenicid on renally excreted penicillins. Furthermore, probenicid has been found to interfere with the renal excretion of frusemide (14) and with the excretion of methotrexate which, in the latter case, may lead to excessively high plasma concentrations of the cytotoxic agent unless the dose is adequately reduced (15).

Table 1. Examples of drugs eliminated by active tubular transport

Acids Bases

Salicylate

Probenecid

Indornethacin Naproxen Mepacrine Penicillins

Sulphonamides Prenalterol Thiazide diuretics Procainamide Loop diuretics Methotrexate

Ethambutol

Mecarnylamine

Pindolol

Partly after Brater ( 1 980) ( 1 1).

Tubular reabsorption

Reabsorption of the primary urine, formed by ultrafiltration in the glomeruli, occurs all along the nephron. About 80-90", of the filtered volume is already reabsorbed in the proximal tubule. Reabsorption of fluid continues in the distal tubule and in the collecting duct so that the urine flow which reaches the renal pelvis only accounts for 1-2 ml/min out of the initially filtered volume of approximately 130 ml/min.

The tubular reabsorption of fluid leads to an increase in the concentration of filtered and/or actively secreted drug molecules in the urine. Due to the concentration gradient, thus formed between the tubular fluid and the capillary plasma water, drug molecules can be reabsorbed by passive diffusion across the lipoidal tubular mem- brane. Factors affecting tubular reabsorption are related to the physicochemical properties of the drug molecule-primarily lipid solubility and the ionization constant-but also physiological variables, such as the urine flow and the pH of the urine, are of importance.

Effect of urine p H . The pH of the urine usually varies between 5 and 8. Many drugs are weak electrolytes with pK, values in this region. Their renal excretion might, therefore, be susceptible to variations in urinary pH, since only the unionized fraction can penetrate the lipid tubular niembrane and be reabsorbed.

The fraction of unionized drug molecules at a certain pH is given by the Henderson- Hasselbalch equation,

342 C. G. Regdrdh

unionized

ionized pH=pK, + log (acids),

or

ionized

unionized pH = pK, + log (bases),

According to these equations the degree of ionization of acids increases with increasing pH of the urine, while for bases an increase in pH causes less ionization.

Not all weak acids and bases demonstrate pH-dependent elimination. The polar- nonpolar character of the neutral drug molecule is of fundamental importance in this respect. This is illustrated by the renal excretion of the three P-adrenoceptor antagonists; antenolol, practolol and propranolol. These weak bases are structurally related to each other and they all have a pK, value around 9.5 but their polar properties differ substantially. The renal excretion of the polar atenolol and practolol is not affected by the pH of the urine while the excretion of the nonpolar propranolol, though very limited, is significantly related to urinary pH (16, 17).

When the pK, of nonpolar basic drugs is close to 6 or below, or when it approaches 12, the pH of the urine will usually have no influence on the renal excretion. In the first case, urine of normal pH contains a significant fraction of unionized drug and this favours extensive reabsorption. In the second case, ionization is so extensive that practically nothing of the tubular content of a drug can be reabsorbed.

The urinary pH is of equal importance for the reabsorption of weak acids though for these compounds changes in the pH of the urine have the opposite effect on the ionization; as compared to that of weak bases. Table 2 lists some weak acids and bases for which urine pH-dependent elimination might have clinical relevance.

Table 2. Drugs wirh clinically important urine pH-dependent elimination

Weak acids Weak bases

Sulphonamidc derivatives Amphetamine

Salicylates

Phenobarbital

Ephedrine N-acctylprocainamide Pseudoephedrine Procainamidc Quinidine Tocainide Tricyclic antidepressants

Partly from Brater (1980) ( 1 1 ) .

Effect of un'nejow. In addition to urine pH, the flow rate may influence the renal excretion of drugs that are reabsorbed in the tubule. Two different mechanisms have

Drug pharmacokinetics I V . Renal excretion 343

been proposed by which the urine flow may affect the renal excretion of drugs. According to one theory, increased urine production diminishes the concentration gradient between the tubular content and the plasma water and this results in reduced back diffusion of drug molecules. The other plausible mechanism is related to the time the drug is available for reabsorption. With greater urine flow, the drug molecules pass the reabsorptive area of the tubule more rapidly and the chance of back diffusion across the tubular membrane decreases. Both these mechanisms suggest that urine flow will only have a significant impact on those drugs that are extensively reabsorbed by the kidney.

RENAL CLEARANCE

As previously mentioned, renal clearance is the result of all three processes discussed above. This can be described by the following equation:

where CI,, is the clearance by glomerular filtration, CIT, expresses tubular secretion clearance and F R is the fraction reabsorbed in the tubule.

Depending on the type of drug, renal clearance may vary between practically zero and a value approaching renal blood flow. The former would be compatible with complete tubular reabsorption of filtered and secreted drug. The high clearance value suggests almost complete extraction from the blood while passing through the kidney, and no tubular reabsorption. Examples of drugs with these extreme renal clearance characeristics are: felodipine ( I 8) and prenalterol(13).

There are several methods by which renal clearance can be assessed. T h e most accurate and informative method, but also the most complicated one, is based on serial determinations of urinary excretion rates and the plasma levels of the drug following intravenous or oral administration. The slope of the regression line, obtained by plotting the excretion rate 2rs the plaPma concentration at the midpoint of the urine collection interval, is equal to the renal clearance (Fig. 2). If the relationship is represented by a curved line or the correlation between excretion rate and plasma level is low, or non-significant, this is an indication of saturable tubular secretion and/or that the renal excretion is affected by urinary pH or flow rate. Instead of using excretion rates and midpoint plasma levels, the amount excreted during serial collection inter- vals plotted vs the areas under the plasma concentration-time curve, during these intervals, will give the same information concerning renal clearance.

Two other methods are so-called one point determinations. One of them is based on a given intravenous dose and the fraction of the dose ultimately excreted via the kidneys in unchanged form, Xu, i.e.

xu,cc Cl,=Cf x -

where Cl, is renal clearance and C f represents total body clearance. The other method determines renal clearance from the ratio between Xu, cc and the total area under the plasma concentration-time curve, AUCco, so that:

344

400.- r \ 0 a f Z 300-. n c .-

0 c

r" - 0

C . G . Regdrdh

/

xu,m AUCm

a,=-

Which of these four methods, that should be used in the individual cases, is very much a practical problem? Undoubtedly the last two methods mentioned are the most simple ones to use but, on the other hand, much information about the renal clearance of a drug can be lost by application of these methods.

T H E E F F E C T OF I M P A I R E D RENAL F U N C T I O N O N T H E E L I M I N A T I O N O F D R U G S

The function of the kidney may deteriorate because of changes in renal blood flow or by diseases affecting the integrity of the glomerulus (nephrotic syndrome) or the number of functioning nephrons. In severe cases, this leads to physiological and biochemical alterations which may significantly alter the response to drug treatment.

Several reviews have been published over the last 10 years which deal with the effect of renal dysfunction on the pharmacokinetics of parent drugs and their metabolites (19-24). Clearly renal impairment causes a multiplicity of changes related to drug kinetics. These changes include, for instance, effects on systemic availability, dis- tribution and binding to plasma proteins and on the rate of elimination from the body. Moreover, since uraemic patients are often treated with several drugs concomitantly,

Drug pharmacokinetics IV. Renal excretion 345

the possibilities of adverse effects due to interactions are greater than in patients with normal kidney function (19). However, in this review article only the effect of depressed kidney function on drug and metabolite excretion into the urine will be considered.

There are two factors of major importance for determining the extent to which renal dysfunction may affect the elimination of a drug and/or its metabolites from the body. These are the fraction excreted via the kidneys in relation to other routes of elimina- tion v,) and the degree of renal impairment. The latter can be expressed as the ratio between the renal clearance in the diseased state Clr,,, and the clearance at normal kidney function, Clr,,. The overall effect of these two factors, on the rate of elimination of various compounds from the body, is given by the equation:

where CI, is the total clearance in the patient with renal insufficiency and Cl, is the total clearance in the healthy individual. It follows from this equation that a drug has to be cleared via the kidneys to at least 500,,, of the given dose before one normally has to consider dosage adjustment because of renal insufficiency. A reduction of renal clearance by 50qh would only decrease total clearance by a quarter of its normal value for a compound with fe = 0.5, and complete renal deficiency would diminish total clearance for such a compound by 503,.

There are two ways to avoid accumulation of renally excreted drugs in patients with moderately to severely impaired renal function (creatinine clearance 25-50 ml/min and <25 ml/min, respectively). I f we assume that the average steady-state drug level, C during a dosing interval, is the same in subjects with normal and impaired renal function, it follows that in the latter:

-

wheref CI, is the total clearance in the patient with renal insufficiency, T is the dosing interval and F stands for the fraction of dose reaching the systemic circulation. The effect o f f (i.e. the ratio between total clearance in the subject with impaired and normal kidney function) on c can be compensated for by a corresponding decrease in the dose, or increased dosing interval, or by a combination of both these factors. Usu- ally a reduction of the dose and maintenance of the same dosing interval, as in patients with normal kidney function, is recommended as this leads to the smallest fluctuation in the plasma concentrations during a dosing interval (Fig. 3). Comprehensive dosing guidelines for adults suffering from decreased renal function have been published by Bennett and associates (25-26).

The kinetics of metabolites eliminated from the body by renal excretion are affected by kidney dysfunction in the same way, and to the same extent, as the kinetics of the parent drug. This is of particular interest as regards pharmacologically active metabolites. The accumulation problem with these metabolites has been discussed by for instance Drayer (24) and Mawer (27).

346

2.0 4

C . G . Regdrdh

1.5

1 .o

0.5

0.0 -I 0 12 24 36 48 60 72

h

Fig. 3. The effect of different dosing strategies in renal insufficiency. Curve 1, healrhy subject: dose = 50 pnol, F = 1 , dosing interval = 12 h, clearance = 77 ml/min, r ! = 3.0 h. Curve I I , patient wirh renal dysfunction: dose 25 pmol, F = 1 , dosing interval = 12 h, clearance =

Curve 111, patient wirh renal dysfunction: dose 50prno1, F = 1, dosing interval 24 h, clearance= 38-5 ml/min, I ! = 6.0 h.

38.5 mlimin, t i =6.0 h.

E L I M I N A T I O N OF D R U G S BY D I A L Y S I S Patients with severely impaired kidney function are subjected to either haemo- or peritoneal dialysis to avoid accumulation of waste products in the body and to maintain electrolyte balance. Dialysis, primarily haemodialysis, is also frequently undertaken in situations of intoxication due to acute intake of an overdose of drugs.

The effectiveness of drug removal by dialysis is determined by several factors related both to the equipment, and to the physicochemical and pharmacokinetic properties of the particular drug. It is beyond the scope of this review to discuss equipment factors or the differences between the two dialysis techniques. Suffice it to say that dialysable substances are usually removed 5 to 10 times more rapidly by haemodialysis as compared to peritoneal dialysis (28).

Dialysance The rate at which a drug is eliminated by the dialyser in haemodialysis is given by

its dialysance (D) which in fact is an expression for the clearance by the equipment, which takes into consideration the incoming drug concentration in the dialysate, C,:

Drug pharmacokinetics IV. Renal excretion f i n

347

LA-% D=Qb-

where Qb is the blood flow over the dialysis membrane and C, and C, are the concentrations of drugs in the affluent and effluent blood of the artificial kidney. When C, < C, this expression can be substituted by:

CA-C"

CA D=Qb-

which is the usual equation for drug clearance by an eliminating organ.

Drug related factors aflecting dialysance

The capacity of the dialyscr, in combination with specific properties of the drug molecule, determines the dialysance in each specific case. As regards the drug, the molecular weight, water solubility and protein binding primarily affects the rate of removal during conventional haemodialysis. Dialyser membranes usually have a pore size smaller than 25A which limits the size of the molecules that can penetrate the membrane, to a molecular weight of about 1500 Daltons (31). According to Babb and colleagues (32), clearance of small molecules ( < 500 Daltons) is significantly influenced by the flow of blood and dialysate and by the effective membrane surface area while the clearance of larger molecules seems primarily to be dependent upon the latter factor.

The effect of water solubility on the clearance of drugs by haemodialysis is less clear. Often very lipophilic drugs are extensively bound to plasma proteins and only a small fraction of the total amount of drug in the body is available in the blood. Both of these factors adversely affect drug removal by haemodialysis and it can be difficult to separate the effect of lipophilicity from the influence of protein binding and volume of distribution.

Since diffusion is the major determinant for the transportation of drug molecules across the dialysing membrane the concentration of unbound, freely diffusible drug is of utmost importance for successful haemodialysis. Clearance decreases with increasing degree of protein binding.

D I A L Y S A B I L I T Y

The clearance of a drug by haemodialysis gives a measure of the rate of removal of drug from the blood but gives no information about the amount of drug removed during a dialysis interval. This information is given by the dialysability of the drug which is defined as the percentage eliminated of the initial amount of drug in the body during haemodialysis (30). Knowledge of the dialysability is crucial for adequate dosage recommendations of drugs given chronically to anephric patients.

In a recent paper, Keller and co-workers (30), studied the effect of molecular weight, protein binding and volume of distribution on dialysability by taking values from 89 drugs in the literature. There was a negative linear correlation between dialysability and plasma protein binding while dialysability increased linearly against the reciprocal of the volume of distribution. However, there was no correlation

348 C. G. Regdrdh

between the molecular weight up to at least 1000 Daltons and the dialysability. According to this study, plasma protein binding was the best predictor of the dialys- ability of the variables studied, but only 2701, of the variance in dialysability could be explained by contribution from these variables. Because of the significant influence of unknown factors to the variation in dialysability, it was stated by these authors, that there is no simple way of reliably predicting dialysability (30). Considering, however, that this conclusion was drawn purely on the basis of literature data, the use of, for instance, different dialyser equipment by different investigators, may have led to a significant under-estimation of the influence of protein binding and volume of dis- tribution on the dialysability. Probably the chances for successful dialysis are rather small for extensively protein bound drugs, >goo$, and for drugs with apparent volumes of distribution exceeding 250 litres.

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