joo Basic Medicinal Chemistry Principles NAME _) -z Metabolism (Dr. Davis) ; ae November 21, 2000 SSN 32 Gow PART L. True/Palse, Indicate whether each ofthe following questions are “tue” by circling the reer TO t's or false” by circling the leter "F". (2 pts each). Alp 1, ‘The oxygen species generated by cytochrome P-450 is highly electrophilic (cleetron- U deficient). T@». In order for a phase-2 metabolic reaction to occur, a phase-1 metabolic reaction must occur first. T®)3. The presystemic ‘frst pass effect’ is based upon the gut flora metabolizing a phase-2 conjugate excreted in the bile “The three major P-450 isozymes responsible for drag metabolism in humans are CYP2D6, CYP2E1, and CYP3A4. ‘Genetic polymorphism’ in metabolism occurs if >1% of the population shows differences in tee meataboliz pathway being considered in comparison to the general population Genetic polymorphism in the metabolism of isonicotinic acid hydrazide (INH, below) is based on differences in the rate of N-acetylation by different populations. —-NHNH, aS Zo N’ 0 F 7. The process of induction is an adaptive process in which enzyme levels can be increased by The process of inc dorepression of transcription and (2) post-translational stebilization of mRNA. t(B)8. Changes in metabolism based on induction and inhibition are typically qualitative rather than quantitative. tion of the P-450 isoform(s) responsible for the metabolism of T Bp. A likely consequence of inhibitior pregnancy. contraceptive steroids woul QF 10. A iikely consequence of induction of the -450 isoform(s) responsible for the metabolism of the anticoagulant warfarin would be clotting.PART Page ; Il. Multiple Choice. Circle the single most appropriate letter [3 pts each] 1. Halogens have a very predictable effect on the hydroxylation of aromatic rings. A & c D. Since they are ring deactivating by an inductive effect, but are gy ca directing by a resonance effect, rings with halogens undergo the ortho/para position. Since they are ortho/para directing by a resonance effect” Dut are ring deactivating by an inductive effect, aromatic rings with halogens generally do not undergo hydroxylation. Since they are ring acivating by an inductive effect, and are ortho/para directing by a resonance effect, rings with halogens undergo aromatic hydroxylation in the ortho/para position. Since they are ring deactivating by an inductive effect, and are meta directing by a resonance effect, rings with halogens undergo aromatic hydroxylation in the meta position. 2. Approximately how many cytochrome P-450 isoforms are present in humans? A D. One. Between five and seven. Between thirty-five and forty. Greater than one hundred. 3. The metabolically-based interaction between alcohol (ethanol) and acetaminophen is based on: c. D. Ethanol-based induction of a P-450 isoform responsible for the metabolism of acetaminophen. Ethanol-based inhibition of a P-450 isoform responsible for the metabolism of acetaminophen. Acetaminophen-based induction of a P-450 isoform responsible for the metabolism of ethanol. Acetaminophen-based inhibition of a P-450 isoform responsible for the metabolism of ethanol. 4, Which one of the following statements concerning the ‘prodrug’ concept is incorrect (false)? A B. D. A prodrug is frequently designed to overcome problems of ‘localized toxicity’ seen with the parent drug (i., the parent drug is toxic while it is present in a particular part of the body; the prodrug is not). A prodrug is frequently designed to overcome problems in tissue distribution seen with the parent drug (e.g., the parent compound cannot enter the requisite tissue or organ; the prodrug can), Prodrug design based on esters is generally a poor idea because of the high variability in esterase activity between individuals (i., there would be a highly variable response between individuals). A prodrug requires metabolism to convert it to the parent drug. 5. Anew drug with an ester functionality has an unacceptably short half-life. Four of your chemist colleagues are coming up with suggestions to prolong the half-life through various molecular modifications. Which one of your colleagues is making an incorrect statement. A B. c. 6) 4 George says “We can slow down the metabolism of the drug if we convert the ester to an amide (provided the amide derivative is still active).” Susan says “We can slow down the metabolism of the drug if we place methyl groups near the ester functionality to increase steric hindrance (provided the derivative is still active). Pam says “We'd better figure out exactly how the drug is metabolized first. If ester hydrolysis isn’t a major pathway for metabolism for this drug, then slowing down ester hydrolysis by chemical modification isn’t going to appreciably increase the half-life.” \None of the above. All of your colleagues are correct in their statements.Page 3 PART Il. PREDICTING METABOLIC PATHWAYS. Directions (READ CAREFULLY): For the reactions specified below, you are to indicate the metabolite(s) formed from the reaction or enzyme specified in the space provided. You need not dravh. the complete structure, only that part which has been changed. If the reaction is not possible, simply write “no reaction” in the box and explain why not. ~ So that there is no confusion (e.g,, “I’m not sure whether the reaction would go because there is already a polar functional group present on the other side of the molecule”) you should use the following eriteria: If the functional group required is present and the reaction is mechanistically feasible, then you can perform the metabolic reaction. If the necessary functional group is not present and/or the reaciion is not mechanistically feasible, you cannot do the reaction. ‘You may find these structures helpful in formulating some of your responses to some of these questions. ° t no. COOH me I HO: SH HO Upp 1. Shown below is the structure of Trimetrexate, a folate antagonist which is approved as an orphan drag for the treatment of Pneumocystis carinii in patients with AIDS. Indicate the structure of the final metabolite that would result from the reaction specified on the parent drug, Trimetrexate. If the reaction is not possible, simply write “no reaction” in the box and explain why not, You need not draw the complete structure, only that part which has been changed (2 pts each]. i H Hi NJ N A None Z | o., CH, Ni HCO fn iy NHy OCH, B. The product resulting from Denaylic hydroxylation of Trimetrexate, followed by the action of alc/aldehyde dehdrogenases: “y ‘A, The product(s) resulting from oxidative deamination of Trimetrexate: Baca 0 a QD 6) +e & i 3