Glucuronidation is often involved indrug metabolism of substances such asdrugs, pollutants,bilirubin,androgens,estrogens,mineralocorticoids,glucocorticoids,fatty acid derivatives,retinoids, andbile acids. These linkages involveglycosidic bonds.[1]
Glucuronidation consists of transfer of theglucuronic acid component ofuridine diphosphate glucuronic acid to a substrate by any of several types ofUDP-glucuronosyltransferase.UDP-glucuronic acid (glucuronic acid linked via aglycosidic bond touridine diphosphate) is an intermediate in the process and is formed in theliver. One example is the N-glucuronidation of anaromatic amine,4-aminobiphenyl, by UGT1A4 or UGT1A9 from human, rat, or mouse liver.[2]
The substances resulting from glucuronidation are known asglucuronides (or glucuronosides) and are typically much morewater-soluble than the non-glucuronic acid-containing substances from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces (via bile from the liver).Hormones are glucuronidated to allow for easier transport around the body. Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of potential therapeutics. Sometimes toxic substances are also less toxic after glucuronidation.
The conjugation of xenobiotic molecules withhydrophilic molecular species such as glucuronic acid is known asphase II metabolism.
Glucuronidation occurs mainly in theliver, although the enzyme responsible for itscatalysis,UDP-glucuronyltransferase, has been found in all major body organs (e.g.,intestine,kidneys,brain,adrenal gland,spleen, andthymus).[3][4]
Various factors affect the rate of glucuronidation, which in turn will affect these molecules'clearance from the body. Generally, an increased rate of glucuronidation results in a loss of potency for the target drugs or compounds.
| Factor | Effect on glucuronidation[5] | Main drugs or compounds affected[5] | |
|---|---|---|---|
| Age | Infant | ↑ | Chloramphenicol,morphine,paracetamol,bilirubin, steroids |
| Elderly | ↑ or unchanged | No change found for paracetamol,oxazepam,temazepam, orpropranolol. Decreased clearance found forcodeine-6-glucuronide, and decreased unbound clearance for oxazepam in the very elderly. | |
| Sex | Females | ↓ | Clearance higher in males for paracetamol, oxazepam, temazepam, and propranolol. Possible additive role with CYP1A2 resulting in higher clozapine and olanzapine concentrations in females |
| Males | ↑ | ||
| Body habitus | Overweight | ↑ | Clearance of lorazepam, oxazepam, temazepam, and paracetamol likely the result of an increase in liver size and quantity of enzyme |
| Underweight/malnourished | ↓ | Chloramphenicol, paracetamol | |
| Disease states | Fulminant hepatitis, cirrhosis | ↓ | Zidovudine, oxazepam, lamotrigine |
| Hypothyroidism | ↓ | Oxazepam, paracetamol | |
| HIV | ↓ | Paracetamol | |
| Tobacco smoking | ↑ | Propranolol, oxazepam, lorazepam, paracetamol. Possible additive role with CYP1A2 induction causing decreased clozapine and olanzapine concentration. | |
Many drugs which are substrates for glucuronidation as part of their metabolism are significantly affected by inhibitors or inducers of their specific glucuronisyltransferase types:
| Substrate | Inhibitors of glucuronidation[5] | Inducers of glucuronidation[5][6] |
|---|---|---|
| Morphine |
|
|
| Oxazepam |
|
|
| Bilirubin |
| |
| Paracetamol |
| |
| Androsterone |
| |
| Carbamazepine- 10,11-transdiol |
| |
| Codeine |
| |
| Lamotrigine |
| |
| Lorazepam |
| |
| Temazepam |
| |
| Testosterone |
| |
| Zidovudine |
|
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