Why drug metabolism makes lipid-soluble drugs water-soluble
Drug metabolism, mainly in the liver, converts lipid-soluble drugs (ones that dissolve easily in fat) into more water-soluble forms that the kidneys can excrete (remove from the body).
Remember
Metabolism turns lipid-soluble drugs into water-soluble ones that the kidney cannot easily take back into the blood, so they can be removed in urine. Inactivating a drug is a common result of metabolism, not its purpose.
Memory aid
oil does not wash out of a cup until it is made to dissolve in water, and the liver does that job for drugs
Think of a fat-soluble drug as oil in a cup: it only leaves once it has been made to dissolve in water.
Most drugs are lipid-soluble enough to enter cells, which helps them cross cell membranes and reach their targets. The same property causes a problem at the end of the journey. The kidney filters the unbound drug (drug not attached to plasma proteins) from the blood at the glomerulus (its tiny filtering unit), but an unchanged lipid-soluble drug passing along the renal tubule (the tube that carries the filtered fluid) slips back into the blood. Very little would reach the urine, so the drug would linger in the body.
Metabolism breaks this loop. It converts the drug into more water-soluble products called metabolites. These are more polar, meaning that they interact readily with water and cross lipid membranes poorly. They cannot easily cross back over the tubule wall, so they stay in the tubular fluid and leave in the urine, and some are excreted in bile. The liver is by far the most important site, although the gut wall, lung and kidneys also contribute.
Metabolism is conventionally divided into Phase I and Phase II reactions. Phase I reactions (oxidation, reduction or hydrolysis, which means splitting a molecule with water) add or reveal a polar group, a part of the molecule that attracts water. Phase II reactions are conjugation, which attaches a water-soluble molecule to the drug. Most drugs undergo Phase I followed by Phase II, but either may occur alone.
Inactivating a drug is a common result of metabolism, but it is not the purpose. Some metabolites stay active, and pro-drugs (inactive until metabolised) such as codeine need metabolism to work.
Key facts
- Purpose
- metabolism makes a drug more polar (more water-soluble) so that the kidneys, and sometimes the bile, can remove it.
- Why it is needed
- an unchanged lipid-soluble drug is taken back into the blood from the renal tubule, so very little is excreted.
- Main site
- the liver, with smaller contributions from the gut wall, lungs and kidneys.
- Two phases
- Phase I adds or exposes a polar group, and Phase II attaches a water-soluble molecule.
- Exceptions
- metabolism usually reduces activity, but pro-drugs are activated by it and some metabolites stay active.
- Not excretion
- excretion only removes the drug or its metabolites from the body and does not itself alter their structure.
Exam traps
- Metabolism does not make a drug more lipid-soluble to help it cross membranes, because it generally reduces lipid solubility, and a more lipid-soluble drug would be taken back from the renal tubule and excreted less well.
- Phase I reactions do not always inactivate a drug, because some products stay active and pro-drugs are activated by them.
- Taking a drug through Phase I and then Phase II is not the aim of metabolism, because the two phases are the method: either may occur alone, and a small number of drugs are excreted unchanged.
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