Question

describe how phase I and phase II metabolism influence/affect i) renal and ii) hepatic elimination of a drug? Answers must be detailed and complete sentences.

Answer 1

Drug elimination is the process of removing administered drugs from the body. Hydrophilic drugs can directly undergo excretion while hydrophobic drugs need to undergo certain metabolic modifications in their molecules. Generally, the liver is responsible for drug metabolism and kidney for excretion so, dysfunction at any level can lead to the accumulation of drug / toxic metabolites. Biotransformation of hydrophobic drugs along with increasing the hydrophilicity also detoxifies the exogenous substances.

2 pathways of hepatic drug transformation are phase I and phase II.

Phase I: Hepatic microsomal enzymes cause oxidation, reduction, and hydrolysis of the exogenous molecules. The cytochrome P450 system is responsible for oxidative metabolism. CYP34A is an enzyme of cytochrome P450 family and is responsible for the metabolism of more than 50% of drugs. The activity of these enzymes can be activated or inhibited by drugs and other substances. Their activation diminishes the activity of the drug and inhibition can increase the drug plasma concentration to toxicity levels. For example, phenytoin and phenobarbital induce the enzyme activity while diltiazem and erythromycin inhibit it.

Phase II: In this phase, polar molecules (like amino acids, glucuronic acid, glutathione, acetate, etc.) are added to the nonpolar group to make them hydrophilic and allow renal/biliary excretion. Molecules can enter bypass phase I and enter directly or may undergo initial processing in phase I. Glucorinidation (UDP-glucuronosyltransferase is the enzyme involved) is one of the main processes for biotransformation. A phase II metabolite of morphine i.e., morphine-6-glucuronide has significant analgesic activity.

Hepatic elimination: The first-pass effect is a feature of hepatic metabolism that plays an important role in the elimination of many drugs. Because of the first-pass effect, enteric drugs directly get transferred to the liver via portal vein where they undergo biotransformation before getting into the systemic circulation. This demands for adjustability in drug dosage as this process reduces the bioavailability of the drug. Drugs administered intravenously escape the first-pass metabolism.

Renal excretion completes the process of drug elimination that started in the liver. Polar molecules undergo filtration and get excreted in the urine. The pH of urine affects the excretion of drugs. Weakly acidic drugs show increased excretion in basic urine and weakly basic drugs in acidic urine.

Clinical Significance

In liver diseases like cirrhosis, phase I and phase II are affected leading to toxic accumulation of the drug/metabolite. So, in case of severe liver disease, the dose of the drug needs to be reduced to have the same effect. Also, in conditions that reduce blood flow to the liver as in shock or hypotension, the drug metabolic rate reduces.

In renal diseases like chronic kidney disease, renal excretion of the drug is compromised leading to accumulation. With increasing age, renal functions become less effective and thus adjustments in dose need to be considered. Certain conditions that affect renal blood flow like congestive heart failure, ADH pathologies also reduce the renal excretion of the drug.