Pharmacokinetics — What the Body Does to a Drug

When you take a medicine, two different stories unfold at once. Pharmacodynamics is "what the drug does to the body" — how it binds its target and produces an effect. Pharmacokinetics is "what the body does to the drug" — how it moves into, around, and out of the body over time. This lesson is about the second story, because the concentration of a drug at its target ultimately decides whether a dose is ineffective, exactly right, or dangerously toxic. Pharmacokinetics is usually summarised by four processes — ADME: - Absorption — how the drug gets from its site of administration into the bloodstream. - Distribution — how it spreads from the blood into the tissues. - Metabolism — how the body chemically alters it, mostly in the liver. - Excretion — how it is finally removed, mostly by the kidneys. Each of these is fundamentally a chemistry problem — it depends on a molecule's size, charge, fat-solubility (lipophilicity), water-solubility, and how readily it crosses membranes. Understanding ADME is what lets doctors choose a sensible dose, decide how often to give it, and predict how a drug's behaviour will change in someone with liver or kidney disease.

Absorption is the journey from the site of administration to the bloodstream. A drug given intravenously skips this step entirely — by definition it is 100% absorbed. Every other route crosses at least one barrier of cells. The oral route is the most common, and chemically the most interesting. A swallowed tablet must dissolve, survive the acidic stomach, and then cross the lining of the small intestine to reach the blood. To cross that membrane, a drug generally needs to be lipophilic enough to pass through the lipid bilayer — recall that cell membranes are built from phospholipids, which form a barrier to charged or strongly water-loving molecules. Bioavailability is the key concept here: the fraction of an administered dose that actually reaches the systemic circulation in active form. Intravenous drugs have a bioavailability of 1 (100%); oral drugs almost always have less, for two reasons: - Incomplete absorption — not all of the drug crosses the gut wall. - First-pass metabolism — blood leaving the intestine travels first to the liver, via the hepatic portal vein, before reaching the rest of the body. The liver can chemically destroy a large fraction of the drug before it ever circulates; some drugs are metabolised so heavily on this "first pass" that they cannot be given orally at all. This is why the same drug often has a much larger oral dose than intravenous dose — the extra oral amount compensates for everything lost to incomplete absorption and first-pass metabolism.

Once in the bloodstream, a drug distributes into the tissues, and how widely it spreads again comes down to chemistry. Lipophilic drugs cross membranes easily and spread widely, even into hard-to-reach compartments. The brain is protected by the blood-brain barrier, an especially tight lining of blood vessels that keeps most water-soluble molecules out. Only a sufficiently lipophilic drug can cross it — which is why a drug meant to act on the brain (a general anaesthetic, many psychiatric medications) must be fat-soluble, while a drug we want to keep out of the brain is often deliberately designed to be water-soluble instead. Plasma protein binding also shapes distribution. Many drugs travel through the blood partly bound to proteins, especially albumin. Only the unbound, free fraction is active and able to leave the blood to reach its target — the bound portion acts as a temporary reservoir. If two drugs compete for the same binding sites, one can displace the other, raising the free concentration of the displaced drug and potentially causing toxicity — an important source of drug interactions. The volume of distribution (Vd) is a calculated value summarising how extensively a drug has spread. A drug that stays mostly in the blood has a small Vd; one that disappears into fat and tissues has a very large one — a single number that captures where a drug "likes" to go.

Most drugs are eventually chemically altered — metabolised, usually in the liver — into forms that are easier to excrete. The central chemical challenge: the kidneys excrete water-soluble substances efficiently, but many drugs are lipophilic and would simply be reabsorbed rather than excreted. The liver's job is largely to convert lipophilic drugs into more water-soluble ones. Drug metabolism is traditionally split into two phases: - Phase I reactions modify the drug — typically by oxidation, reduction, or hydrolysis — often adding or exposing a chemically reactive group. The most important players are the cytochrome P450 (CYP) enzymes, a large liver enzyme family responsible for metabolising a huge proportion of all drugs. - Phase II reactions attach (conjugate) a bulky, water-soluble molecule onto the drug, making it far more water-soluble and usually inactive, ready for excretion. Metabolism usually inactivates a drug, but not always. A prodrug is deliberately given in an inactive form, designed to be converted by the body's own enzymes into the active drug — improving absorption or allowing more controlled activation. The CYP system is a major source of drug interactions: some substances inhibit these enzymes, slowing the metabolism of other drugs and raising their levels (grapefruit juice is the famous example), while others induce them, speeding metabolism and lowering drug levels — sometimes to the point of treatment failure. Genetic differences between individuals in these enzymes also explain why an identical dose can affect two people very differently.

The final step is excretion — removing the drug, and its metabolites, from the body. The kidneys are the main route: blood is filtered, and water-soluble drugs and metabolites pass into urine. This is why metabolism aims to make substances water-soluble, and why patients with kidney disease often need reduced doses — they clear drugs more slowly, so standard doses can accumulate to toxic levels. Some drugs are also excreted in bile and lost in faeces, and small amounts can leave via sweat, breath, or breast milk. Half-life is the single most useful pharmacokinetic number in practice — the time taken for a drug's blood concentration to fall by half. It drives two key clinical decisions: - How often to dose — a short half-life demands frequent dosing to maintain useful levels; a long half-life allows once-daily (or less frequent) dosing. - How long effects last — after stopping a drug, it takes roughly four to five half-lives to be almost completely cleared. Steady state is reached when the rate of drug going in (dosing) equals the rate being removed (clearance), so the average concentration stays roughly constant. Reaching it takes about four to five half-lives of regular dosing — which is why some medications take days to reach their full, stable effect even though you start taking them immediately. For drugs with a narrow therapeutic window, where the effective dose and the toxic dose sit close together, these calculations become critical, and blood levels are sometimes measured directly — therapeutic drug monitoring — to keep the concentration safely within range.