Metabolism and excretion

Question 1

Metabolism - prednisone first-pass, bioavailability

Answer 1

when taken orally, the drug is absorbed in the intestines, when it is absorbed from the lumen of the GI tract into the hepatic portal system. From here it undergoes first-pass metabolism in the liver, by the action of the enzyme 11-β hydroxysteroid dehydrogenase, to become pro-drug prednisolone. The first pass effect does not significantly affect prednisolone’s bioavailability (70%). The half-life of prednisolone is 2-3 hours and is longer in people with liver disease due to lower albumin levels

Question 2

Phase 1 Metabolism

Answer 2

Prednisolone is primarily metabolized in the liver, where it enters through the hepatic portal vein. Inside the liver, hepatocytes contain CYP3A4 which is part of the CYP450 family. CYP3A4 plays a significant role in the oxidative and reductive metabolism of prednisolone. Oxidation converts drug molecules into more polar or water-soluble metabolites. CYP3A4 converts prednisolone into less active metabolites, such as 6β-hydroxy-prednisolone, which are then further processed for elimination from the body.

Question 3

Metabolism
Phase II metabolism

Answer 3

Prednisolone undergoes Phase II metabolism, to excrete any molecules which are still too polar or lipid soluble.
Conjugation with sulfate and glucuronic acid, make the molecules more water-soluble and polar ready for excretion.

Question 4

Inducers

Answer 4

certain drugs such as carbamazepine and phenytoin increase the activity of CYP3A4, increasing metabolism and possibly reducing effectiveness of prednisolone.

Question 5

Inhibitors

Answer 5

Inhibitors such as Ketoconazole and Itraconazole decrease the activity of CYP3A4, slowing down metabolism, leading to increased plasma concentration and increased duration of action, which could lead to an increased risk of side effects.

Question 6

glomerular filtration rate (GFR) decreases Excretion Process

Answer 6

conjugated metabolites enter the kidney through the bloodstream and are filtered at the glomerulus into the urine.
The polar nature of the conjugated metabolites prevents them from being reabsorbed into the bloodstream through renal tubules.
98% of prednisolone is excreted in the urine as inactive conjugated metabolites, through passive diffusion.
2% may also be eliminated through biliary excretion into the feces.
Renal elimination of drugs decreases with age due to a reduced glomerular filtration rate (GFR), slowing drug clearance by the kidneys, increases the risk of drug accumulation and toxicity in older adults.