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D:\pha4120-5127\PROBLEMS\ANSWERS\5127_answers\ans-problems_metabolism.doc 1PHA 5127Problem Set"Drug Metabolism"1. Tilidine is a narcotic analgesic which can be abused by drug addicts when taken in highdoses. Naloxone is an opiate antagonist which blocks the action of tilidine. It is knownto undergo a saturable first pass effect. What is the rationale for a drug combinationtilidine/naloxone (valoron)?Answer:Low dose (therapeutic dose)Naloxone is metabolized by first-pass effect and does not affect the analgesic action of tilidine.High dose (addicts)The first-pass-effect for naloxone is saturated. Naloxone inhibits the euphoric action of tilidine.Rationale: Combination is useful for therapeutic use with little abuse potential.D:\pha4120-5127\PROBLEMS\ANSWERS\5127_answers\ans-problems_metabolism.doc 22. Administration of phenobarbital (60 mg daily) to a patient receiving dicumarol (75 mgdaily) chronically, reduces the plasma concentration of the anticoagulant ( l ) and theprothrombin time ( m ), a measure of its effect on the concentration of the vitamin k1-dependent clotting factors.What kind of pharmacokinetic interaction is responsible for the observedpharmacodynamic interaction? Explain your answer.Answer:Note:1)Dicumarol is an anticoagulant2)Prothrombin time is a measure of its effect3) Phenobarbital is an inducer of P450. This increases the metabolism ofdicumarol.From 45-75 days phenobarbital is given. This induces the metabolism of dicumarol, thusdecreasing its concentration. As the concentration of dicumarol decreases, it will be easier forthe blood to coaglulate. Hence, the prothrombin time (which is directly related to the timenecessary for the blood to coagulate) will decrease. After 75 days the phenobarbital is notgiven hence we see the rise of dicumarol concentration and hence an increase in prothrombintime. After 160 days again phenobarbital is given causing again a decrease in dicumarolconcentration and after phenobarbital administration is stopped (i.e. after 170 days) theconcentration of dicumarol rises. Note that as the 2nd duration of phenobarbital administrationis less, the overall decrease in dicumarol concentration for the second time is also less.D:\pha4120-5127\PROBLEMS\ANSWERS\5127_answers\ans-problems_metabolism.doc 33. Discuss following statement: For drugs with a hepatic extraction ratio of 1, thehepatocyte does not represent a strong diffusion barrier.Answer:for E = 1, 100% of the drug needs to be metabolized. If there is a strong diffusion barrier,100% of drug cannot enter. Thus E does not equal 1, hence contradicting the statement.4. Select for the following physiological changes the induced change on thepharmacokinetic parameters for a lipophilic, protein bound, low extraction drug clearedby liver and kidney.Physiological change effect on kinetics1. increase in plasma protein_____ a. Cltot 2. increase in blood flow____ b. Vd 3. decrease in metabolic liver enzymes____ c. Vd 4. decrease in creatinine clearance_____ d. khep/kren 5. increase in the number of fat cells_____ e. Clint 6. blood flow at the absorption site_____ f. Clhep g. none of the above effectAnswer:1. increase in plasma protein Vd decreases (b)2. increase in blood flow none of the above3. decrease in metabolic liver enzymes Clint decreases (e)4. decrease in creatinine clearance khep/kren increases (d)(Not covered until "Excretion")5.increase in the number of fat cells Vd increases (c)6. blood flow at the absorption site none of the above (g)D:\pha4120-5127\PROBLEMS\ANSWERS\5127_answers\ans-problems_metabolism.doc 45. Mark whether the following statements are True or FalseT F gut wall metabolism is one example of the first-pass effect.T F enterohepatic recycling can prolong drug activity in the body.T F biliary obstruction decreases the half-life of a drug subject to biliaryexcretion.T F most drugs only pass through the liver once.T F if hepatic blood flow is reduced, more drug will get


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UF PHA 5127 - Drug Metabolism

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