DRUG CLEARANCE
Clearance is defined as the rate of drug elimination divided by the plasma
concentration of the drug.
Drug clearance is influenced by age and by disease, with a reduction in drug clearance
being associated with an increase in the half-life of the drug, and an increase in
clearance being associated with a decrease in the half-life of the drug.
TOTAL DRUG CLEARANCE
Drug clearance involves both the processes of metabolism and excretion.
Metabolic - or hepatic - clearance is the conversion of the parent drug into a different
chemical entity by liver enzymes, particularly the cytochrome P450 family of enzymes.
It is dependent on a number of factors, including: hepatic blood flow, the rate of liver
enzyme activity and the rate of secretion into the bile. Anything which impacts on these
factors (eg. competition between drugs for the metabolising enzymes in the liver,
or genetic polymorphisms which alter the activity of these enzymes) may, in turn,
impact on drug clearance, either speeding it up or slowing it down.
The key point to remember about metabolism is that it makes drugs less lipid soluble,
more water soluble, and therefore easier to excrete from the body.
Renal clearance, on the other hand, is the removal of the drug from the body by the
kidneys. It is dependent on a number of factors, including: renal blood flow, and the
rates of glomerular filtration and tubular secretion compared to the rate of passive
diffusion. (Lipid soluble, or un-ionised drugs will undergo passive diffusion, being
reabsorbed into the blood stream; ionised drugs will be retained within the tubule.)
Anything which impacts on these factors may impact on drug clearance, either speeding
it up or slowing it down.
Relative importance of metabolism and excretion in drug
clearance
The relative importance of metabolic and renal clearance differs, depending on the
drug. Some drugs undergo mainly metabolic clearance, and others undergo mainly
renal clearance.
One of the key factors which determine the importance of hepatic vs renal clearance is
a particular drug's lipid solubility, or degree of ionisation..
As cell membranes are lipid in nature, lipid soluble (or un-ionised) drugs can readily
cross them. These drugs will enter hepatocytes (or liver cells), and are likely to
undergo extensive hepatic clearance.
However, if a drug is ionised, it will not be able to cross the membranes of liver cells
easily. Therefore, this drug will be less likely to undergo hepatic metabolism, and more
likely to undergo extensive renal clearance. Examples of drugs cleared almost entirely
by the kidneys are furosemide and atenolol.
RENAL DRUG CLEARANCE
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.
HEPATIC DRUG CLEARANCE
Two commonly used models of hepatic drug clearance are examined. The “well-stirred” model
(model I) views the liver as a well-stirred compartment with concentration of drug in the liver
in equilibrium with that in the emergent blood. The “parallel tube” model (model II) regards
the liver as a series of parallel tubes with enzymes distributed evenly around the tubes and the
concentration of drug declines along the length of the tube. Both models are examined under
steady-state considerations in the absence of diffusional limitations (cell membranes do not
limit the movement of drug molecules). Equations involving the determinants of hepatic drug
clearance (hepatic blood flow, fraction of drug in blood unbound, and the hepatocellular
enzymatic activity) and various pharmacokinetic parameters are derived. Similarities and
differences between the models are explored. Although both models predict similar hepatic
drug clearances under a variety of conditions, marked differences between them become
apparent in their predictions of the influence of changes in the determinants of drug clearance
on various pharmacokinetic parameters.