Pharmacokinetics

Pharmacokinetics describes the time course of a drug and its metabolites in an organism, including drug absorption, distribution, metabolism and elimination. A concentration-time curve helps distinguish exposure from response: equal administered amounts can produce different concentrations at the target.

Drug clearance relates the rate at which a drug is eliminated to a specified measured concentration:If elimination is 10 mg/h at a plasma concentration of 2 mg/L, clearance is 5 L/h. This is an effective volume per time, rather than the physical volume of fluid actually removed. The concentration reference, such as plasma or whole blood, must be specified. ^[ref]

For constant clearance and a one-compartment distribution volume $V$, the amount $A=VC$ obeys $dA/dt=-CLA/V$. Thus $k=CL/V$ and $t_{1/2}=V\ln 2/CL$. The derivation explains why a longer half-life can reflect greater distribution volume as well as lower clearance; half-life and clearance are not interchangeable measurements.

Drug metabolism chemically transforms a drug into other molecular forms. Oxidation, hydrolysis and conjugation are common routes, frequently involving the liver but also other tissues. Transformation may inactivate a compound, generate an active product or activate a precursor; metabolism therefore does not mean detoxification in every case. ^[ref]

The parent compound and each product have their own time courses. In a simple pathway $D\to M\to$ further products, a fall in $D$ can coexist with a rise in an active metabolite $M$. Measuring only the parent can therefore misrepresent pharmacologically relevant exposure. Chemical conversion, excretion of unchanged material and movement into a different tissue are distinct processes.

Drug elimination removes a parent drug from the body's measured parent-drug pool through drug metabolism or excretion. Redistribution from blood to a tissue changes plasma concentration but does not by itself eliminate the drug from the body. A mass balance separates input, output and transfers between compartments. ^[ref]

For a one-compartment model with no input and first-order elimination, $dA/dt=-kA$ gives $A(t)=A(0)e^{-kt}$. Equal fractions disappear in equal time intervals. By contrast, a saturated elimination route can approach removal of equal amounts per interval. The latter produces a different concentration-time curve and cannot be assumed to have a concentration-independent half-life.

Drug distribution is movement of a drug between blood and other body compartments. Perfusion, membrane permeability, tissue binding and plasma-protein binding jointly affect it. The apparent distribution volume iswhere $A$ is the amount in the body and $C_p$ the plasma concentration. If $A=100$ mg and $C_p=2$ mg/L, $V_d=50$ L. ^[ref]

The result is a proportionality quantity, not an anatomical cavity that must contain that many litres. Extensive tissue binding can lower $C_p$ and make $V_d$ large. A rapid fall in plasma concentration immediately after administration can therefore reflect distribution as well as drug elimination; distinguishing them requires a model and a suitable sampling schedule.

Transfer of a drug from its administration site into the systemic circulation. Direct intravenous delivery bypasses this transfer step.