Assignment 6 Metabolism A drug is eliminated almost exclusively by hepatic metabolism via glucuronidation and subsequent excretion into the bile. The excreted glucuronide is neither hydrolyzed in nor reabsorbed from the intestines. The volume of distribution and half-life of the drug are 100 L and 9 hrs, respectively.

Glucuronides are usually pharmacologically inactive. 1. Like this drug, all glucuronides of drugs are inactive and eliminated via the bile or kidney. Is this statement true or false? Why? The statement is false. Inactive: Glucuronides are usually pharmacologically inactive. Does not apply to glucuronides of all drugs. Examples: i) Conjugates generated by acyl glucuronidation of NSAIDs. (toxic metabolite) ii) Activation of morphine (pharmacologically active metabolite) What is glucuronidation? Glucuronidation is a type of conjugation reaction, which is an example of a Phase II metabolism pathway.

Example 1: Conjugates generated by acyl glucuronidation of NSAIDs. UDP-glucuronosyltransferase,UGT2B7 (microsomal enzyme) UDP Glucuronic acid (endogenic substance) Prrotein reactive metabolite which may cause toxicity in some patients.

Example 2: Activation of morphine Glucuronidation at the 6-OH position results in the formation of an active metabolite

1. Like this drug, all glucuronides of drugs are inactive and eliminated via the bile or kidney. Is this statement true or false? Why? Eliminated: Not 100% of glucuronidated drug excreted in bile will undergo elimination as some may be hydrolyzed and reabsorbed in intestines. Thus, this will contribute to the distribution of the drug. This recycling process is called ‘Enterohepatic Cycle’

Example: Morphine-3-glucuronide Deconjugation/hydrolysis Morphine-3-glucuronide Morphine Morphine-3-glucuronide undergoes enterohepatic cycle. This explains the high initial dose of morphine usually administered, followed by lower maintenance doses.

1. Like this drug, all glucuronides of drugs are inactive and eliminated via the bile or kidney. Is this statement true or false? Why? Bile or kidney: This is true as glucuronide conjugates are generally hydrophillic Excretion of glucuronide conjugates is also promoted by the carboxylic acid moiety of the glucuronic acid, which increases the aqueous solubility of the conjugate. Specific transporters at the membranes between: i) liver and bile ii) renal capillaries and renal tubules

1. Like this drug, all glucuronides of drugs are inactive and eliminated via the bile or kidney. Is this statement true or false? Why? Bile or kidney: Increased MW of drug due to glucuronidation. As a guideline, drug MW >350g/mol is needed to ensure high biliary clearance. Whereas for kidney, drug MW with anything less than 60000g/mol and not bounded to proteins will be filtered.

2. What is the hepatic extraction of this drug? Hepatic blood flow is 1.5L/min. Rate of elimination = CL x C Since, C = Ab/V Rearranging, Rate of elimination = (CL/V) x Ab k is the fractional rate of drug elimination Thus, k = Rate of elimination/Ab = CL/V Also, k = 0.693/t1/2 Thus, t1/2 = 0.693/k = (0.693/CL) x V Thus, 9hrs = (0.693/CL) x 100L CL = 7.7L/hr However, this is CLtotal. But, since it is stated that drug is eliminated almost exclusively by hepatic metabolism, CLtotal = CLhep

Hepatic CL = Rate of elimination/CA = QH(CA-CV)/CA = QH x EH Thus, 7 Hepatic CL = Rate of elimination/CA = QH(CA-CV)/CA = QH x EH Thus, 7.7L/60min = 1.5L/1min x EH EH = 0.086

3. Is the clearance of this drug more likely to be sensitive to a change in plasma protein binding or a change in hepatic perfusion? Known: This drug has a low hepatic extraction ratio. Change in hepatic perfusion: Rate of elimination remains unchange with hepatic perfusion changes. Thus, hepatic clearance remains unaltered. Therefore, clearance of this drug is not sensitive to changes in hepatic perfusion.

3. Is the clearance of this drug more likely to be sensitive to a change in plasma protein binding or a change in hepatic perfusion? Change in plasma protein binding: Rate of elimination = CLu x Cu Divide equation with C, CLH = CLu x fu An increase in fraction unbound of drug in plasma will cause an increase in hepatic clearance of this drug, while the intrinsic clearance of liver remains unchanged. Therefore, clearance of this drug is sensitive to changes in plasma protein binding.