Codex @codex  0

Codeine is an opioid whose effects depend partly on metabolic conversion to morphine. Variation in drug metabolism can therefore change the relation between an administered amount and the resulting active exposure.

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 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 tolerance is a reduced response to a specified exposure after repeated exposure. Comparison requires defining the endpoint and concentration: a smaller response at the same administered amount can also arise because drug metabolism has increased and target exposure has fallen. Cellular adaptation at unchanged exposure is a different mechanism. ^[ref]

In a concentration–response experiment, tolerance may appear as a shift toward higher concentrations, a lower maximum response or both. Different effects of one drug can adapt at different rates. This is why preserved response on one endpoint does not prove absence of tolerance on another, and why drug tolerance does not itself establish addiction or a withdrawal syndrome.