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Pceut532_Final_2005 - 1<7 3 ‘\C at 1 Fill in the...

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Unformatted text preview: 1 <7 3; ‘ \C at 1. Fill in the Blanks or Circle the correct answer. ‘ A. (2 pts) The incidence of the slow acetylator phenotype in the Asian population is 10-30% and the incidence in the Caucasians and African- American population is 40—70% . B. (2 pts) The incidence of the poor'metabolizer phenotype of CYP2D6 in the Caucasian population is _6-10%_ and in the Asian population it is < 2% C. (2 pts) The incidence of the poor metabolizer phenotype of CYP2Cl9 in the Caucasian and African-American population is 2-5% and in the Asian population it is 12-35% . D. (2 pts) A case report documented that a person who was an ultrametabolizer of CYP2D6 had significant toxicity after receiving several doses of codeine suggesting that morphine was responsible for the toxicity. E. (2 pts) What is a commonly used drug metabolized by CYP2C19 with dose dependent efficacy that is significantly greater in poor metabolizers than in extensive metabolizers? Omeprazole, lansoprazole or pantoprazole F. (2 pts) ED had been receiving a low dose of nortriptyline every day for 3 _ months. Nortriptyline is metabolized by CYP2D6 to an inactive metabolite. His clinician added fluoxetine. If you knew that ED was a poor metabolizer of CYP2D6, what would you expect his plasma concentrations of nortriptyline to do? (Increase, decrease or remain the same G. (2 pts) A group of 100 Caucasian subjects were phenotyped for CYP2D6; however, they were also taking fluoxetine The majority of the subjects will be phenotyped as poor metabolizers If they were genotyped, the ma] ority would be extensive metabolizers H. (2 pts) A CYP2C9*2/ *2 (poor metabolizer) would have a phenytoin Vmax that 13 (greater, _l__ess or the same) as a CYP2C9*l/*1 (extensive metabolizer) ' ' I. (2 pts) The Asian and African— American population have a higher incidence of decreased affinity alleles of CYP2D6 than does the Caucasian population. True or False J. (2 pts) Debrisoguine or dextromethorphan is a probe for phenotyping CYP2D6 and caffeine or dapsone or sulfmethazine is used as a probe to phenotype NAT2 2. (4 pts) List the 4 major therapeutic classes that have several drugs that are extensively metabolized by CYP2D6. i. analgesics iii. antipsycotics ii. antidepressants iv. cardiovascular drugs ' 3. (5 pts) Isoniazid causes peripheral neuropathy in NAT2 slow acetylators. Explain why reducing the dose in slow acetylators can decrease the incidence of toxicity comparable to the incidence found in fast acetylators. For slow acetylators lempa < lemPa in fast acetylators Therefore Clearance (Cl) is less in slow acetylators than fast acetylators TFm (toxic) = Q3; (toxic) since Cl is less in slow acetylators, Fm is greater tel TFm (toxic) = TM (toxic) If dose is the same in slow and fast acetylators then Dose slow acetylators have greater amounts of M By reducing the dose of isoniazid in slow acetylators proportional to the decrease in the total clearance, the fast and slow acetylators produce the same amount of toxic metabolite. <—> M (toxic) = TFm" Doseiv 4. (4 pts) Using the concept of gene-dosing, complete the graph of concentration vs. time that you would expect to find in 4 people who have reCeived a single oral dose of a drug significantly metabolized by CYP2D6 and are either 1) a homozygous poor metabolizer 2) a heterozygous extensive metabolizer 3) a homozygous extensive metabolizer 4) an ultrametabolizer of CYP2D6. Concentration Time 5. (3 pts) List three diseases that are associated with decreased serum albumin concentrations. (HINT: contrary to some folklore, age and pregnancy are not diseases). i) renal disease cancer malnourished ii) liver disease traumatic injury iii) burn analbuminemia 6. (4 pts) A lactating mother is prescribed amoxicillin for a urinary tract infection. She wants to know whether or not her 6-month—old son will have measurable levels of amoxicillin if she takes the drug while breast-feeding. Amoxicillin is 30% bound to plasma proteins. What can you tell her? For drugs that are greater than 90% protein bound, the infant will not have measurable concentrations of the drug if breast—fed. Since amoxicillin is only 30% protein bound, the infant will have measurable concentrations of amoxicillin. 7‘ Given the following equation for the oral clearance of gabapentin, answer the following questions. Q1 = 1.61* (CrCl) + 3.6 F Normal Gabapentin concentrations: 2—10 ug/ml A. (2 pts) What does the 3.6 represent in the equation describing the oral clearance of gabapentin? How important is this to the oral clearance of gabapentin? The 3.6 represents the non-renal component of the total clearance. For a person is a normal creatinine clearance of 100-120 ml/min, the 3.6 only represents a small fraction of the clearance. Even when a' person has a low creatinine clearance (i.e. 30ml/min), the 3.6 is still just a small fraction of the total clearance of gabapentin. During pregnancy, total plasma concentrations of phenytoin decline due to T Fu due to Jr albumin and T hepatic metabolism. Pharmacokinetic differences between males and females are reported in the product label for a large number of drugs. Correcting for body weight decreases the number of drugs with significant sex—dependent differences. ' 9. Fill in the Blank with increase (T), decrease (Jr) or the same or no change (<——>) or circle correct answer. (1 pt each) A. Albumin serum concentrations are Jr in neonates, <—) in children and Jr in the elderly compared to healthy adults. In general, cytochrome P450 activity is Jr in neonates, T in children and Jr in the elderly compared to healthy adults. In general, glucuronidation is Jr in neonates, <-—) in children and (—> or J in the elderly compared to healthy adults. For valproate, a low extraction ratio drug that is eliminated my hepatic metabolism, a decrease in albumin will result in a Jr in total concentration and (—9 in unbound concentrations. Liver cirrhosis can result in a significant Jr in the first pass metabolism of high extraction drugs. 10. True or False A. (2 pts) The effect of age on the activity of CYP2C9 is different than the effect of age on the other CYP isozymes. True False__X (2 pts) Renal function in a child will reach adult levels by approximately 4 years of age. True False X (2 pts)A patient with acute hepatitis with significantly elevated liver function tests will require a decrease in the doses of drugs metabolized by CYP450 but not drugs metabolized by glucuronidation. True False X B. (6 pts) CS is a 79—year male (70kg) with serum creatinine of 2.0 mg/dl. He has been prescribed 300 mg twice daily. Calculate what his average steady state concentration of gabapentin will be if he takes the gabapentin as prescribed. (140 - Age) - (LBW) CrC1(m1/Inin) = -"—“"""‘— = (l40-79)*70 =29.65 nil/min 72 o SCr —-——-—-——— (72)(2.0) g =1.61*(CrC1)+3.6 = (1.61)*(29.65)+3.6 =51.34m1/min F Css = F*(Q/‘c) = 1600 ngd)*§1day/24hr1*11hr/6O min) = 8.1 mg/L C1 (51.32 ml/min)*(lL/1000ml) C. (2 pts) You now know that CS had just gone into acute renal failure that ’ day when his CrCl was estimated using a serum creatinine. Would your Css estimate be correct, too high or too low ? The estimate will be low Why? The serum creatinine has not had time to increase to its new steady state that would occur. Fill in the Blanks or Circle correct answer (2 pts each) A. CYP3A4 is a CYP isozyme with activity greater in females than males. B. CYP1A2 is a CYP isozyme with activity E in females than males. C. When females and males intake the same amount of ethanol, females have initial higher plasma concentrations clue to a sex-difference in the liver metabolism of ethanol. True or False D. (2 pts) Cirrhosis significantly decreases the activity of CYP2D6 and CYP3A4 more than the other isozymes. True False X 11. Use the following information if needed to answer the following questions. Phenytoin: VB=0.6 L/kg F = 0.9 S = 0.92 Therapeutic Range: 10 - 20 ug/ml total phenytoin or 1 — 2 ug/ml unbound phenytoin A. (5 pts) M is an 85-year-old 50 kg female with a new onset seizure disorder. Calculate an oral loading dose of sodium phenytoin to target a phenytoin plasma concentration of 16 lag/ml. Describe the appropriate dosage regimen. The following labs are available: Albumin 3.0 gin/d1 Scr = 1.0 mg/dl LD = V 0 (C desired - C observed) =_(0.6L/k 50k 16 mcr/L = 580 mg S 0 F (O.9)(0.92) Give 400 mg sodium phenytoin and then in 3 hours give 180 mg more B. (5 pts) LH is a 40—year-old 85-kg male with a history of complex partial seizures. He arrives in your clinic with nystagrnus and ataxia. Admitting p labs including a positive ethanol level, albumin plasma concentration of 2.8 gin/d1 and a total phenytoin plasma concentration of 18 ug/ml. You are asked to rule out ethanol vs. phenytoin intoxication. ll [PHT . ] = [PHT] total normahmd 0.25[Alb] + 0.1 = 18 gmel = 22.5_ pig/ml It is above the therapeutic range and is (0.25)*(2.8)+0.1 probably the cause of the CNS effects. A new drug is known to exhibit Michaelis Menten elimination pharmacokinetics. The average pharmacokinetic parameters for this drug in an adult are: Vmax: 80 mg/day Km: 13.2ng/mL = 0-0‘32‘Mj/mL 2 0,0!32 “ff/‘— Oral bioavailability: 100% a. (3 points) Calculate the average drug concentration at plateau for a patient taking 20 mg orally each day. "cf”— ‘M'FD — w ?JIVMQL— FD 1d . gong/Cr — [,0» 20m? : o.oo44~o_-_m_g .: 4"4—Qj/ML L— b. (7 points) A different patient has been taking this new drug at a daily oral dose of 40 mg day for several months and his average plateau drug level is 14.0 ng/mL. His daily dose is then increased to 50 mg orally per day. Several months later his average plasma drug level was again measured and found to be 26.4 ng/mL. What are this patient’s individual Vmax and Km? You may use the graph paper supplied. 40 ms . 40M3/cl ‘ 285-7 L/pl ’3- 0,OI4_mJ/,_ ‘ so :2; mag/cl : raw: L/cl 6‘ 0-0294‘MJ/L, K r—SIOF8=_ AV :‘AhOMJS/d‘ YOMJ/A. IOM3/cl m 2’" 1957 L/QL - (8‘14 L/cI 453 L/A _ h lav/“3H, : O¢0I04~ :13 :; IO.4— n5 .K Chafing/L L— mt. ‘ ‘ mefi, intercept g 68' 70 J (actualw I ‘ at MS (DR is dosing rate) In Chi IADEC Tn le‘t—l I‘M/\f‘r‘ rr-rvmu: 51W ...
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