B1-DRUG-METABOLISM-2015 - Drug Metabolism Consequences of...

This preview shows page 1 out of 39 pages.

Unformatted text preview: Drug Metabolism Consequences of drug metabolism CYPs and Transporters Reading: Katzung, Chapter 4 Pay special attention to Tables 4.1 - 4.4 1 B1-DRUG-METABOLISM-2015 - February 5, 2015 2 B1-DRUG-METABOLISM-2015 - February 5, 2015 Reduction and hydrolysis reactions for metabolism of warfarin 3 B1-DRUG-METABOLISM-2015 - February 5, 2015 Example of conjugation of salicylic acid to form the salicylic glucuronide 4 B1-DRUG-METABOLISM-2015 - February 5, 2015 CYP nomenclature Isoform is of human origin Isoform family Isoform subfamily Individual gene product in the subfamily CYP 1 A 2 Refers to a human cytochrome P450 isoform of the first family that is a member of the A subfamily of enzymes and is the second gene product assigned to that subfamily. 5 B1-DRUG-METABOLISM-2015 - February 5, 2015 Drug-CYP450 interactions • Promote drug elimination • Promote drug activation • Inhibition of drug metabolism can • Prolong drug action • Allow drug concentrations to reach toxic levels • Drugs can induce their own metabolism • Drugs can increase metabolism of co-administered drugs • Induction can lead to production of toxic metabolites • Influence of GI bacteria 6 B1-DRUG-METABOLISM-2015 - February 5, 2015 CYP3A CYP2D6 CYP2C CYP1A2 CYP2E1 • Many drugs use more than one CYP • These pathways are saturable • CYP3A - lots of inhibitors and inducers • CYP2D6 - genetic variants, e.g., codeine – 10% of caucasians – Chinese produce less morphine from codeine • CYP2C9: genetic variants, e.g., warfarin • 10-20% caucasians have a variant isoform • Can’t inactivate warfarin efficiently; thus, more sensitive to the drug 7 B1-DRUG-METABOLISM-2015 - February 5, 2015 CYP450 induction G-&-G, Chapter 6 8 B1-DRUG-METABOLISM-2015 - February 5, 2015 Consequences of CYP450 induction Drugs can induce their own metabolism Carbamazepine Induce CYP3A4 Metabolized by CYP3A4 Drugs can increase metabolism of coadministered drugs Carbamazepine + diazepam Rifampin + saquinavir G-&-G, pp. 94-97 9 B1-DRUG-METABOLISM-2015 - February 5, 2015 CYP450 reaction and inhibition Reaction Inhibition Da ✘ Di Di ✘ Da Golan, Figure 4.4 10 B1-DRUG-METABOLISM-2015 - February 5, 2015 Hydroxylation reactions Pentobarbital Promotion of renal drug excretion by increasing drug polarity 11 B1-DRUG-METABOLISM-2015 - February 5, 2015 Metabolic inactivation Phase I Phenobarbital Phase II p-Hydroxyphenobarbital 12 p-Hydroxyphenobarbitalglucuronide B1-DRUG-METABOLISM-2015 - February 5, 2015 Evolution of procaine-like antiarrhythmic agents Procaine ↑ Threshold of ventricular muscle Antiarrhythmic agent Rapidly hydrolyzed by ChE enzymes in vivo Procainamide N-Acetylprocainamide Similar effects as procaine Antiarrhythmic agent Resistant to hydrolysis by ChE enzymes 60-70% dose excreted unchanged 20% acetylated by Nacetyltransferases enzymes t½ = 2.5-fold longer than procainamide 13 B1-DRUG-METABOLISM-2015 - February 5, 2015 Propranolol 4-Hydroxypropranolol active Naphthyloxylacetate inactive 14 B1-DRUG-METABOLISM-2015 - February 5, 2015 Metabolism of acetaminophen leading to toxicity Glutathione L-Cysteine 15 B1-DRUG-METABOLISM-2015 - February 5, 2015 Sequential steps in drug metabolism N-Dealkylation Diazepam Hydroxylation Nor-Dazepam Oxazepam Phase II Conjugation Renal Elimination 16 B1-DRUG-METABOLISM-2015 - February 5, 2015 Metabolic conversion to more active, less toxic metabolite Terfenadine (SELDANE™) Fexofenadine (ALLEGRA™) 17 B1-DRUG-METABOLISM-2015 - February 5, 2015 Examples of enzyme induction 18 B1-DRUG-METABOLISM-2015 - February 5, 2015 Consequences of CYP450 inhibition Inhibition of drug metabolism can Prolong drug action Allow drug concentrations to reach toxic levels • Ketoconazole Ritonavir Inhibits 3A4 But this can be used to advantage Ritonavir + Lopinavir What are the advantages of this combination? 19 B1-DRUG-METABOLISM-2015 - February 5, 2015 Drug-Nutrient Interactions ‣ Grapefruit juice ‣ Inhibits CYP3A4 ‣ Inhibits 1st-pass metabolism of co-administered drugs CYP3A4 Felodipine Aromatized (oxidized) felopidpine (PLENDIL™) Grapefruit juice Alcohol Felodipine ∼ Grapefruit juice Felodipine 20 >> Felodipine B1-DRUG-METABOLISM-2015 - February 5, 2015 drug therapy 100% 15% Felodipine dose 45%* Felodipine bioavailability Liver Portal vein 100% Small bowel Gut lumen A B Enterocyte CYP3A4 30% 100% Hepatocyte Sinusoid 45%* 15% CYP3A4 90%* Inhibition Grapefruit juice 30% 90%* Figure 1. First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its Interaction with Grapefruit Juice. CYP3A enzymes (e.g., CYP3A4) present in enterocytes of the intestinal epithelium extensively metabolize felodipine during its absorption, and on average only 30 percent of the administered dose enters the portal vein (solid line). Subsequently, CYP3A enzymes in the liver further metabolize the drug so that only 15 percent of the dose is bioavailable and finally reaches the systemic circulation and is able to exert its effects. Grapefruit juice selectively inhibits CYP3A in the enterocyte, with the net result being an increase in the oral bioavailability of felodipine by a factor of three, denoted by the asterisks and the dashed lines. Wilkinson, NEJM, 352, 2211-2221 (2005) dosage strategy for clinical situations. Moreover, drug interactions involving updated information about drug interactions is inhibition of cyp3a available on a number of Web sites (e.g., www. themedicalletter.com, , Inhibition of the metabolism of one drug by the adof , and www. dition 21 another causes problems, since plasma B1-DRUG-METABOLISM-2015 - February 5, 2015 drug concentrations may rapidly increase after one imm.ki.se/CYPalleles/). Bacterial reduction in gut to produce drug activation (inactive) Reduction by GI bacteria Sulfanilamide (active) Prontosil 22 B1-DRUG-METABOLISM-2015 - February 5, 2015 Bacterial reduction in gut to produce drug inactivation Reduction by E. lentum Digoxin Dihydrodigoxin 23 B1-DRUG-METABOLISM-2015 - February 5, 2015 Two structurally-unrelated drugs bound to active center of CYP450 Ketoconazole Erythromycin 24 B1-DRUG-METABOLISM-2015 - February 5, 2015 Characteristic Properties of CYP Enzymes Metabolism + Elimination ➨ Duration of drug action Saturable Broad range of substrates Inhibitable Inducible Temperature-sensitive 25 B1-DRUG-METABOLISM-2015 - February 5, 2015 Genetic Polymorphisms 26 B1-DRUG-METABOLISM-2015 - February 5, 2015 Isoniazid • 1912: Synthesized • 1952: Used as treatment for TB • 1953: Adverse reactions reported – Peripheral neuropathies • numbness, pain, tingling in arms-legs of some patients – Source of toxicity of Isoniazid • Interfered with vitamin B6 (pyridoxine) • ↓ Degradation of ISO ← impaired acetylation • Genetic deficiency of N-acetyltransferase 27 B1-DRUG-METABOLISM-2015 - February 5, 2015 N-Acetyltransferase 2 polymorphism b 24 Subjects (number) 267 subjects 60 e number e1 90 18 Fast acetylators for NAT2 Slow acetylators for NAT2 12 6 0 0 4 8 12 Plasma isoniazid concentration (mg/ml) Plasma concentrations of isoniazid in 267 subjects 6 h after administration of tyrylcholinesterase (BCHE) genetic variation. The figure shows data for 135 members of 7 an identical oral a proband shown. The bimodal frequency ated families selected on the basis ofdose arewith atypical BCHE. These subjects were distribution results otyped for percentage inhibition of BCHEin the NAT2 gene.homozygous for the trait of from polymorphisms by dibucaine. Subjects al BCHE are shown at the far left. (b) N-acetyltransferase 2 genetic variation. Plasma Weinshilboum and Wang (2006) are Rev. Human Genetics, Figure 1b ntrations of isoniazid in 267 subjects 6 h after administration of an identical oral dose Ann.shown. Weinshilboum (2003) NEJM bimodal frequency distribution results from polymorphisms in the NAT2 gene. Modified from ences 32 and 59. 28 B1-DRUG-METABOLISM-2015 - February 5, 2015 Polymorphisms in CYP 2D6 Debrisoquine Sparteine Nortriptyline β-Blockers Codeine Dextromethorphan 29 B1-DRUG-METABOLISM-2015 - February 5, 2015 R. L. Smith, 1977 • Debrisoquine • Antihypertensive agent • Smith and his colleagues tested themselves with high doses of debrisoquine • Colleagues recovered quickly • Smith suffered marked and prolonged hypotension and dizziness 30 B1-DRUG-METABOLISM-2015 - February 5, 2015 Genetic polymorphism in debrisoquin 4hydroxylation by CYP2D6 • • • Their urine showed the usual metabolite expected of debrisoquine Smith’s did not Examined 94 volunteers • • • Poor metabolizers Extensive metabolizers Ultrarapid metabolizers 31 B1-DRUG-METABOLISM-2015 - February 5, 2015 e expressed cDNA e activity.20 Using LP patterns in PMs e identification of was published in itful collaboration n RFLP pattern in dicative for PMs in he most common , CYP2D6*10.24 As ntification of the ed several different wer density of the ch we thought had 25 for further deigin revealed that for debrisoquine xtra CYP2D6 gene ut to be the first gene in humans26 Ms) was defined.27 ncies in different 8 10% in Spaniards d Turkey, whereas CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*17 and CYP2D6*41. Table 2 An estimation of the number of ultrarapid CYP2D6 metabolisers in Western Europe carrying two or more active CYP2D6 genes on one allele. The overall percentage in the population is 5.45% Million inhabitants Austria Belgium Denmark England Finland France Germany Greece Holland Italy Norway Portugal Spain Sweden Total Frequency UMs Million UMs 8 10 5 60 5 60 82 10 15 57 5 10 40 9 0.04 0.03 0.01 0.03 0.01 0.04 0.04 0.1 0.03 0.1 0.01 0.1 0.1 0.01 0.32 0.3 0.05 1.8 0.05 2.4 3.28 1 0.45 5.7 0.05 1 4 0.09 376 20.49 Ingelman-Sundberg (2005) Pharmacogenomics J. 5, 6-13. 32 B1-DRUG-METABOLISM-2015 - February 5, 2015 Impact of these discoveries • Oxidation is an important / widespread metabolism reaction • Represents a “polymorphism” • Frequently occurring genetic alteration • Not a rare defect • Medical consequences are not uniform • Over-response • Under-response 33 B1-DRUG-METABOLISM-2015 - February 5, 2015 Homework for Tuesday 10 February 2015 34 B1-DRUG-METABOLISM-2015 - February 5, 2015 Piroxicam, a nonsteroidal anti-inflammatory agent, has a half-life of 40 hours. If it is administered once daily, i.e., every 24 hours, how many doses will it take to reach steady state? A. 1 dose B. 3 doses C. 5 doses D. 8 doses E. 12 doses 35 B1-DRUG-METABOLISM-2015 - February 5, 2015 Qing Zhang, a 22-year-old college student, was taking drug X, but was experiencing little to no benefit from the drug. Which one (or ones) of the following statements is/are possible explanations for this failure of pharmacotherapy? A. He was given the standardized ED50 (mg/kg body weight) but required a higher dose. B. He was a rapid metabolizer of the drug. C. He was given a pro-drug and he was a poor metabolizer. D. All of the above are correct. 36 B1-DRUG-METABOLISM-2015 - February 5, 2015 We did an open-label study in healthy volunteers. The study was approved by the National Institute of Allergy and Infectious Diseases (NIAID) Institutional Review Board, and all participants gave written informed consent. Inclusion criteria included negative HIV-1 test, age over 18 years, The following figure from Piscitelli et al. [Lancet, 355, 547-548 (2000)] limits, and a laboratory values within established NIAID normal physical examination. Volunteers were excluded if illustrates the plasma concentration-versus-time plot ofpast year, received St John’s wort indinavir, an HIV they had smoked in the anti-protease agent, alone and when within 30 days, hadin history of allergy orof St. reactions administered a the presence adverse to indinavir, were pregnant or lactating, were John’s wort (see the figure legend). What can be concluded from these receiving data? Indinavir concentration (µg/mL) A. Indinavir inhibited the metabolism of St. John’s wort. B. Indinavir is a prodrug and St. John’s wort inhibited its activation. C. The time course of indinavir in the presence of St. John’s wort was prolonged. D. St. John’s wort inhibited the metabolism of indinavir. E. St. John’s wort induced the metabolism of indinavir. 14 12 10 8 6 4 2 0 0 1 2 3 4 Time (h) Mean concentration-time of indinavir alone (solid line) and with concomitant St John’s wort (dotted line) 5 again re stomach indinav 5 h afte wort wi concent perform modific calibrat ng/mL coefficie Indin accordin (WinNo USA). (Cmax), concent from tim (CL/F). AUC extrapo log-line concent indices compar mean A alone w estimate Eight the stu Their a time pr THE LANCET • Vol 355 • February 12, 2000 37 B1-DRUG-METABOLISM-2015 - February 5, 2015 RE: Drug distribution. Explain why smoking cocaine leads to a more rapid response than snorting or nasal administration of cocaine. What is the “first-pass” effect? What are the advantages / disadvantages of the following routes of administration? Oral Sublingual IV Topical Transdermal 38 B1-DRUG-METABOLISM-2015 - February 5, 2015 When these agents are administered with rifampin (which induces hepatic drug-metabolizing enzymes) what happens to the relative clearance of V and P? Verapamil & Phenytoin Elimination through metabolism in liver CL(Verapamil) = 1.5 L/min (equal to liver blood flow) CL (Phenytoin) = 0.1 L/min 1. Clearance of both V and P will be increased. 2. Clearance of both V and P will be decreased. 3. Clearance of V will be unchanged, whereas clearance of P will be increased. 4. Clearance of P will be unchanged, whereas clearance of V will be increased. 39 B1-DRUG-METABOLISM-2015 - February 5, 2015 ...
View Full Document

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture