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Application of knowledge about the core pharmacokinetic parameters of bioavailability, distribution volume, protein binding, half-life and elimination helps to optimise drug therapy
Jörg Brüggmann
Dr rer nat
Chief
Pharmacy Department and Regional Drug Information Centre
Accident and Emergency Hospital of Berlin
Germany
Pharmaceuticals number among the most important therapeutic measures for restoring and maintaining health. In order to ensure an effective therapy devoid of side-effects, precise knowledge about the active substances and the form in which the drug is administered is vital. The plethora of substances that are currently available often complicates a meaningful appraisal of the contribution that individual active components make to a therapy.
The pharmacokinetic properties of a substance and the relationship of these pharmacokinetics to the desired effect or side-effect is often not considered adequately.
However, an optimally effective and safe therapy can only be realised if one is aware of the duration and quantity of direct drug exposure that is required to bring about a therapeutic effect.
Knowledge of the pharmacokinetics of a drug serves above all to allow individualisation of therapy, since drugs should ideally be administered in a manner tailored to the individual patient.
For the simple case in which no alterations of physiological parameters are apparent and/or if the simultaneous intake of several medications is not necessary, the drug is usually prescribed according to the specialist information supplied by the manufacturer.
These days, however, most drugs are administered in combination to polymorbid and usually older patients.
Because of functional disruptions of various body organs, and potential interactions between the drugs, complex situations can arise whose consequences cannot be adequately predicted without knowledge of the drugs’ pharmacokinetics.
This article explains the role of important pharmacokinetic parameters in everyday clinical situations. There are of course exceptions to these scenarios, as is the case with all rules.
Bioavailability
Drugs given orally can only exert their pharmacodynamic effects if the active substance is present at a sufficient concentration and for a certain period of time at its site of action.
A measure for this is the bioavailability (BA) of an active substance. In its strictest sense, the term bioavailability refers to the proportion of administered drug that reaches the systemic circulation and which is then available to exert the pharmacodynamic effect. The BA is as such usually expressed as a percentage of the dose. Other definitions consider the rate of absorption and the concentration at the site of action.
The scenarios set out in Table 1 are of practical importance.
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A high bioavailability (eg, > 80%) implies that the active substance is almost completely released from its galenic form, that the released drug is dissolved and absorbed and that during the first passage through the small intestine and liver no significant losses occur due to metabolism (see Figure 1). In optimal cases substances with a high BA indicate a high absorption rate and a low pre-systemic (breakdown by membranous enzymes) and systemic (breakdown by hepatic enzymes) first-pass effect.
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A high bioavailability is also an indicator of the pharmaceutical quality and reliability of a medicinal form. This is of practical importance, particularly where generic preparations are being considered for prescription.
Table 1 illustrates some commonly-used drugs that have high bioavailability.
A low bioavailability (< 40%) implies that only a small percentage of the active substance is absorbed into the circulation before it exerts its effect. A number of mechanisms may underlie a low bioavailability:
- Poor release and solubility in the intestine.
- Metabolism by intestinal bacteria.
- Poor penetration through the mucosa.
- Metabolism within the enterocytes of the small intestine or in the liver (presystemic and systemic first-pass effect).
For substances with a low BA, an oral dose must be considerably higher than a parenteral dose. Because of the pronounced first-pass effect, propranolol, for example, must be administered at 40–80 mg when given orally, but when given parenterally a dose of just 1 mg is sufficient. For everyday clinical practice it must be remembered that drugs with a low BA suffer large interindividual variations in bioavailability, giving rise to unexpectedly high or low drug levels. A high first-pass effect can also be associated with pharmacokinetic interactions dependent on metabolism (see Table 2).
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The bioavailability is also of practical relevance when deciding on the bioequivalence of generic preparations. Two drugs are pharmaceutically equivalent if their bioavailabilities after provision of the same molar dose resemble one another in such a way that the drugs are essentially equivalent with regard to efficacy and harmlessness. An affirmed bioequivalence is therefore an essential precondition for allowing a safe switching between and to generic preparations.
Volume of distribution
The volume of distribution (V) of a medication is an abstract parameter and is defined as the amount of drug in an organism divided by its plasma concentration. After distribution of the drug within the organism, the volume of distribution is computed as follows:
V = m (total amount of drug [mg])
c (drug plasma concentration [mg/l])
The formula can be easily understood if one considers that concentration (c) represents the quotient of the mass (m) and the volume (V).
c = m/V V = m/c
Only for a few medications, however, does the distribution volume correspond to a real physiological space, such as:
- The plasma volume (0.05 l/kg).
- The extracellular volume (0.2 l/kg).
- The body water (0.66 l/kg).
This is due on the one hand to the accumulation of many medications in various tissues, such as the adipose tissue or the bones (producing an increase in the numerator), and on the other to the avid binding with plasma proteins that prolongs the persistence of the agent within the vascular system (producing an increase in the denominator). Both are properties resulting from the solubility and the plasma-protein binding of a medication and which are constant only for one particular patient. Interindividual differences depending on the amount of body fat or body water must also be taken into consideration.
Knowledge of the distribution volume of a medication is of interest because with larger distribution volumes (> 1 l/kg) the phenomena set out below achieve practical significance.
In the case of intravenous injection or rapid absorption, the medication distributes itself first of all in a central compartment and only then throughout the whole distribution volume, that is, into the peripheral compartment. The consequence of this is redistribution within the entire organism. For such medications two half-lives are often provided, namely the distribution half-life (first phase) and the elimination half-life (second phase). With large distribution volumes there is a tendency towards a long terminal half-life, ie the larger the distribution volume, the longer the terminal half-life.
The macrolide antibiotic azithromycin (V = 30 l/kg) achieves, for example, a 50-fold higher concentration in the tissue than it does in the plasma. Because of this disproportionately high tissue affinity, high levels are reached in target tissues such as the lung, tonsils and the prostate. The terminal half-life in the tissues is 2–4 days. As such, one can only administer doses once daily and for a duration of just three days in all.
Unlike the macrolides and quinolones, beta-lactam-antibiotics distribute themselves mainly in the extracellular space. As such they can access a large number of pathogens (pneumococci, enterobacteria) that also occur extracellularly (see Figure 2). Chlamydia, legionella and mycobacteria, on the other hand, also persist intracellularly, and macrolides and quinolones, which can penetrate the cell membrane, are effective against these pathogens (see Figure 2).
The larger the volume of distribution of a drug is, the less effective are detoxification measures such as haemodialysis and haemoperfusion. This becomes a problem for distribution volumes greater than 2 l/kg and indeed an insurmountable obstacle at distribution volumes greater than 5 l/kg. On the other hand, a large distribution volume contributes to a lower elimination of such substances when haemodialysis is carried out so that these agents need not be topped up (see Table 3).
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It must be considered when administering drugs that with advancing age the muscle mass decreases and the body fat increases. As such, lipophilic substances can show a larger distribution volume. The half-life lengthens and there is a risk of accumulation. In the case of diazepam the agent has a half-life of approximately 20 hours in a 20-year-old patient, whereas in a 70-year-old patient the half-life is approximately 70 hours.
For lipophilic substances the much larger distribution volume with advancing age correlates directly with the half-life. Because of the smaller volume of tissue water, hydrophilic medications have a smaller distribution volume, which can result in higher concentrations at the site of action and as such an increase in adverse drug reactions.
Together with drug concentration in the steady state, the distribution volume is of decisive importance for determining the initial dose (loading dose). An initial “saturation dose” is useful when the medication has a long half-life, since four or five half-lives may elapse before a steady-state concentration is achieved.
Protein binding
Substances which dissolve poorly in water can only be transported in the blood if they are bound to plasma proteins. Weak acids mainly bind to albumin and weak bases bind mainly to alpha-1-acid glycoprotein. The protein binding is reversible (an equilibrium exists between the free and the bound fraction of the drug) and is usually of practical importance only in the following scenarios:
- Where very high protein binding occurs (> 90%), since only then are interactions due to displacement of protein binding of clinical interest.
- When the displacing medication is protein-bound and present at a relatively high molar concentration.
- The distribution volume (V) must also be relatively small (< 0.5 l/kg) and the displaced substance must have a narrow therapeutic range.
One example is the displacement of phenprocoumon by diclofenac.
The clinical relevance is comparatively small, however, since the concentration increase is only transient. Usually a balancing with the free concentration in the tissue occurs and with increases in the free concentration the clearance also increases.
When plasma concentrations of medications are measured, only the total concentration – that is, the sum of free and bound medication – is usually measured. However, only the free, and not the bound fraction, is pharmacodynamically effective. If this free fraction increases, these considerations can be important, for example when comparing the plasma concentrations of antibiotics with the minimal inhibitory concentrations (MICs).
The antibiotic ceftriaxone, for example, is highly protein-bound, at 95%. Due to the delayed renal clearance resulting from this (only the free portion is filtered by the glomerulus), a single dose is sufficient over 24 hours to exceed the MIC values. The plasma protein binding of ceftriaxone is concentration-dependent. With an increase in concentration the extent of protein binding decreases and the free, effective fraction increases disproportionately. For an intensification of the therapy administration of a single 4 g dose every 24 hours is more effective than two 2 g doses administered at 12-hour intervals.
Only the free fraction of a medication can be removed by glomerular filtration in the kidneys or dialysed. A medication with low protein binding is therefore more susceptible to glomerular filtration and effective elimination by haemodialysis.
With age the plasma albumin concentration decreases and with that also the degree of protein binding. A higher free substance fraction resulting from that is counteracted in the case of phenytoin by the raised whole body clearance so that this phenomenon is not usually therapeutically relevant.
Plasma half-life
As far as the elimination of active substance is concerned, the time that elapses until the amount of medication is reduced to a half is what we refer to as the half-life. Measurements are usually taken from plasma samples so that we usually talk about the plasma half-life. Awareness of the half-life of an active substance allows an estimate to be made of the duration of an effect from a single dose. The half-life is thus the most important parameter for deciding on a dosing regime. Figure 3 shows that half-life is in fact a derived pharmacokinetic parameter. The half-life lengthens with a large distribution volume and shortens with a large total clearance. For clinical purposes the aspects set out below are important (see Figure 3).
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If the half-life is considerably shorter than the dosing interval, periods of ineffectiveness might arise. Conversely, if the half-life is much longer than the dosing interval, a risk of accumulation within the organism arises as well as the risk of concentration-dependent adverse drug reactions.
As a rule, a doubling of a dose prolongs the effect duration only by a single half-life. If an intensification of the therapy is required with short half-life medications, it does not usually make sense to apply larger doses. Instead, a more frequent application of the medication is more effective.
If both the peak concentration of an antibiotic in the organism and the minimum inhibitory concentration for the pathogen are known, the duration of effect of the antibiotic can be calculated using the half-life. The protein binding should also, of course, be considered here. The same applies for the duration of effect of other types of medication as well.
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Elimination
Awareness of the elimination pathways for medications empowers the doctor to make certain predictions for patients with hepatic or renal impairment.
An extended effect or even an accumulation of the medication can be expected where impaired elimination occurs under certain circumstances. The role of interactions resulting from enzyme induction or inhibition can also be more easily understood. In practice one proceeds as set out below.
The total clearance of a drug consists of the renal clearance and the extra-renal clearance (see Figure 3). For most medications the latter can be equated with hepatic clearance. As a rule one can assume that renal insufficiency only reduces the renal clearance and that liver disease only impairs the extra-renal clearance.
The renal portion of the total clearance results from the so-called renal dose fraction, ie from that portion of an administered dose that is eliminated unchanged via the kidneys.
With impaired renal function only this portion of the total clearance is affected. As such, if the renal dose fraction and the creatinine clearance are known (this is usually an estimated clearance calculated from serum creatinine using the Cockroft and Gault formula or the MDRD formula), one can individually estimate any possible alteration of the total clearance of a medication, and calculate the necessary dose modification. In practice the Q0 values are often used for defining renal elimination:
Q0 value = extra-renal dose fraction
1-Q0 value = renal dose fraction
If the Q0 value of a drug is 0.5–0.3 (renal elimination 50–70 %), the renally eliminated fraction is so large that a dose reduction must be implemented if renal function is substantially impaired (creatinine clearance of 30 ml/min).
The extra-renal portion of the total clearance results from the so-called extra-renal dose fraction, ie the proportion of an administered dose that is not eliminated renally in an unaltered form. With impaired liver function (eg with hepatic cirrhosis but still normal kidney function), only this part of the total clearance is affected. Here one must consider that primarily oxidation reactions, hydroxylations and demethylations are restricted, while conjugation reactions (eg, glucuronidations) often remain intact since they also occur extrahepatically.
Pharmacokinetic interactions related to metabolism can be caused by enzyme induction or enzyme inhibition. The hepatic oxidative cytochrome-P450 system plays a special role here. Only the extra-renal, as opposed to the renal, clearance is affected by this. If one is aware of the extra-renal dose fraction, the potential clinical relevance of an interaction with enzymes can be estimated on an individual basis. Medications with a high first-pass effect, such as beta-receptor blockers, are particularly affected.
Summary
Dosing errors constitute approximately 50−60% of all medication errors and, as such, number among the most frequent medication errors that might be of clinical relevance for the patient. Prevention of such errors therefore represents an important task of the dispensing pharmacist in pharmaceutical healthcare.
Knowledge of the relationships between the core pharmacokinetic parameters of bioavailability, distribution volume, plasma protein binding, half-life and elimination and their practical therapeutic importance represents an important component of this task. In this way errors can be avoided and the potential of the drug can be exploited to the full.
Knowledge of these core pharmacokinetic parameters and their application to clinical routine contributes considerably to the provision of an optimal pharmaceutical therapy. ■
Bibliography
Derendorf H, et al. Pharmakokinetik. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2002.
Langguth P, et al. Biopharmazie. Weinheim Wiley-VCH; 2004.
Jaehde U, et al. Lehrbuch der klinischen Pharmazie. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2003.
Sörgel F, et al. Pharmazie in unserer Zeit 2006;35:438.
EMEA. Note for guidance on investigation of bioavailability and bioequivalence. London: EMEA; 2001.
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