What is meant by non-linear pharmacokinetics? What causes non-linear pharmacokinetic behaviour? equation 1
In most dosing situations, total clearance (CL) is determined by protein binding and intrinsic clearance (CLint) (Article 4 - `How drugs are cleared by the liver' Aust Prescr 1990;13:88-9). equation 2 CL = fu x CLint where fu is the fraction unbound to protein. Combining equations 1 and 2, the determinants of Css during chronic dosing are equation 3
1. Saturation of elimination mechanisms causes a change in intrinsic clearance Drug metabolism equation 4
In pharmacokinetic terms, v is equivalent to the rate of elimination (v = Cu x CL) and S is equivalent to the unbound drug concentration (Cu). Equation 4 can then be rearranged to give a function for intrinsic clearance (see also equation 1). equation 5
Usually, unbound plasma drug concentration (Cu) in the therapeutic range is very small compared to the Km for the metabolising enzyme and equation 5 approximates to equation 6
Fig. 1). In this situation, CLint decreases as unbound drug concentration increases (see equation 5) and steady state drug concentration increases more than proportionately with dose (equation 3). At high drug concentrations, the maximal rate of metabolism is reached and cannot be exceeded. Under these conditions, a constant amount of drug is eliminated per unit time no matter how much drug is in the body. Zero order kinetics then apply rather than the usual first order kinetics where a constant proportionof the drug in the body is eliminated per unit time. Some examples of drugs which exhibit non-linear kinetic behaviour are phenytoin, ethanol, salicylate and, in some individuals, theophylline. Phenytoin: Phenytoin exhibits marked saturation of metabolism at concentrations in the therapeutic range (10-20 mg/L) (Fig. 2). Consequently, small increases in dose result in large increases in total and unbound steady state drug concentration. As an example, for a patient with typical Km of 5 mg/L (total drug) and Vmax of 450 mg/day, steady state concentrations at doses of 300, 360 and 400 mg/day would be 10.0, 20.0 and 40.0 mg/L respectively (Fig. 2). Thus, small dosage adjustments are required to achieve phenytoin concentrations in the therapeutic range of 10-20 mg/L. A second consequence is that, because clearance decreases, apparent half-life increases from about 12 hours at low phenytoin concentrations to as long as a week or more at high concentrations. This means that i. the time to reach steady state can be as long as 1-3 weeks at phenytoin concentrations near the top of the therapeutic range ii. in the therapeutic range, the phenytoin concentration fluctuates little over a 24 hour period allowing once daily dosing and sampling for drug concentration monitoring at any time between doses iii. if dosing is stopped with concentrations in the toxic range, phenytoin concentration initially falls very slowly and there may be little change over a number of days. Alcohol: Alcohol is an interesting example of saturable metabolism. The Km for alcohol is about 0.01 g% (100 mg/L) so that concentrations in the range of pharmacological effect are well above the Km. The Vmax for ethanol metabolism is about 10 g/hour (12.8 mL/hour) and it can be calculated (see legend to Fig. 2) that at the common legal driving limit of 0.05 g%, the rate of alcohol metabolism per hour is 8.3 g/hour. This amount of alcohol is contained in 530 mL light beer, 236 mL standard beer, 88 mL wine or 27 mL spirit. Higher rates of ingestion will result in further accumulation. Renal excretion 2. Saturation of first pass metabolism causing an increase in bioavailability 3. Saturation of protein binding sites causing a change in fraction of drug unbound in plasma equation 7
What are the practical consequences of saturable protein binding? From equation 3, it can be seen that as fu increases, total drug concentration at steady state decreases. However, fu does not affect the steady state concentration of the unbound drug. In other words, unbound concentration will increase linearly with dose, but total drug concentration will increase less than proportionately. This is illustrated in Fig. 3 for the case of disopyramide. This dissociation between total and unbound drug concentration causes difficulties in therapeutic drug monitoring where total drug concentration is nearly always measured. Total drug concentration may appear to plateau despite increasing dose (Fig. 3) leading to further dose increases. However, unbound concentrations and drug effect do increase linearly with dose - if this is not realised, n appropriate dose increases with consequent toxicity can occur. |