cyp450 system

1. By Dr. sriram.r CYP 450 SYSTEM

2. INTRO The  cytochrome P450  is a superfamily of mono- oxygenases Heme -containing enzymes OR hemoproteins Officially abbreviated as  CYP Is a large and diverse group of enzymes that catalyze the oxidation of organic substances They absorb light at a wavelength of 450 nm

3. INTRO (CONTD.)   The substrates of CYP enzymes include – 1. lipids and steroidal hormones 2. Xenobiotics such as drugs and toxic chemicals CYPs are the major enzymes involved in drug metabolism and bioactivation , accounting for about 75% of the total number of different metabolic reactions

4. SITE Present throughout the body Act primarily in the ER of the hepatocytes and the cells of the intestine Conditions that cause viral hepatitis or cirrhosis will affect the efficiency of drug metabolism by the CYP enzymes

5. P450 IN HUMANS Human CYPs are primarily membrane-associated proteins located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells Some CYPs metabolize only one (or a very few) substrates, such as  CYP19  ( aromatase ), while others may metabolize multiple substrates

6. (CONTD.) Humans have 57 genes and more than 59  pseudogenes  divided among 18 families of cytochrome P450 genes and 44 subfamilies.

7. DRUG METABOLISM CYP enzymes account for 75% of drug metabolism Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body. Also, many substances are bioactivated  by CYPs to form their active compounds.

8. DRUG INTERACTION Many drugs may increase or decrease the activity of various CYP isozymes Inducing the biosynthesis of an isozyme (enzyme induction) Directly inhibiting the activity of the CYP (enzyme inhibition) This is a major source of adverse drug interactions

9.  If one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels Hence, these drug interactions may necessitate dosage adjustments or choosing drugs that do not interact with the CYP system  Drug interactions are especially important when using drugs of vital importance to the patient, drugs with important side-effects and drugs with small therapeutic windows

10. Consequences of Induction Increased rate of metabolism Decrease in drug plasma concentration Enhanced oral first pass metabolism Reduced bioavailability If metabolite is active or reactive, increased drug effects or toxicity

11. Therapeutic Implications of Induction Most drugs can exhibit decreased efficacy due to rapid metabolism but drugs with active metabolites can display increased drug effect and/or toxicity due to enzyme induction Dosing rates may need to be increased to maintain effective plasma concentrations

12. Consequences of Inhibition Increase in the plasma concentration of parent drug Reduction in metabolite concentration Exaggerated and prolonged pharmacological effects Increased liklihood of drug-induced toxicity

13. Therapeutic Implications of Inhibition May occur rapidly with no warning Particularly effects drug prescribing for patients on multidrug regimens Knowledge of the CYP450 metabolic pathway provides basis for predicting and understanding inhibition

14. GENETIC VARIATION and its implication Wide variability in the response to drugs between individuals Consequences of such variation may be therapeutic failure or an adverse drug reaction Genetic diversity is the rule rather than the exception with all proteins, including drug metabolizing enzymes

15. CYP2D6 is extensively studied, the gene for CYP2D6 is highly polymorphic It’s expression leads to 3 phenotypes (phenotype is the expression of genetic make-up) Extensive metabolizers ( EMs ) have functional enzyme activity Intermediate metabolizers ( IMs ) have diminished enzyme activity Poor metabolizers ( PMs ) have little or no activity 5-10% of Caucasians and 1-2% of Asians exhibit the PM phenotype

16. CONCEPTS Substrate - An agent that is metabolized by an enzyme into a metabolic end product and eventually excreted Inhibitor - An agent which interferes with the ability of a given enzyme to metabolize a given substrate (Competitive or allosteric ). This leads to RAPID increase in levels of the substrate. Inducer - An agent which causes an increase in the production of the enzyme(s) responsible for metabolizing a given substrate. Leads to GRADUAL (1-3 weeks) decrease in blood level of substrate.

17. DRUG-DRUG INTERACTION PATTERNS ‹ Pattern 1 - An inhibitor is added to a substrate. Example: Paroxetine is added to nortriptyline , leading to an increase in the nortriptyline blood level. Pattern 2 - A substrate is added to an inhibitor. Example: Nortriptyline is added to paroxetine , leading to a higher than expected blood level of nortriptyline at a given dose.

18. Pattern 3 : An inducer is added to a substrate. Example: Carbamazepine is added to haloperidol, leading to a decrease in the haloperidol blood level. Pattern 4 : A substrate is added to an inducer.  Example: Haloperidol is added to carbamazepine leading to a lower than expected blood level of haloperidol at a given dose.

19. Pattern 5 : Reversal of inhibition. An inhibitor and a substrate have been stably co--administered and then the inhibitor is discontinued. Example: Cimetidine is discontinued in the presence of nortriptyline , leading to a decrease in the nortriptyline blood level.

20. Pattern 6 : Reversal of induction. An inducer and a substrate have been stably co-administered and then the inducer is discontinued Example: A patient on clozapine abruptly discontinues smoking, leading to an increase in the clozapine blood level.

21. THE ENZYMES „ 3A4 „„ 2D6 „„ 1A2 „„ 2C9 „„ 2C19 „„ 2E1 „„ 2B6

22. 3A4 Notable Substrates ‹‹ alprazolam , triazolam ‹‹ aripiprazole ‹‹ carbamazepine ‹‹ methadone ‹‹ pimozide ‹‹ quetiapine ‹‹ risperidone ‹‹ tertiary amine TCAs (IMI, AMI, etc.) ‹‹ zolpidem / zaleplon

23. 3a4 Notable inhibitors ‹‹ azole antifungals ‹‹ ciprofloxacin/ norfloxacin ‹‹ fluoxetine / fluvoxamine ‹‹ grapefruit juice ‹‹ HIV protease inhibitors ‹‹ macrolide antibiotics (except azithromycin ) ‹‹ methadone ‹‹ nefazodone

24. 3a4 Notable inducers ‹‹ barbiturates ‹‹ carbamazepine ‹‹ modafinil ‹‹ oxcarbazepine ‹‹ phenobarbital ‹‹ phenytoin ‹‹ ritonavir ‹‹ St. John’s wort ‹‹ topiramate

25. 2d6 Notable substrates ‹‹ amphetamines amphetamines ‹‹ ß-blockers ‹‹ codeine →morphine ‹‹ hydrocodone → hydromorphone ‹‹ phenothiazines ‹‹ TCAs ‹‹ tramadol ‹‹ venlafaxine

26. 2d6 Notable inhibitors ‹‹ bupropion ‹‹ cimetidine ‹‹ duloxetine ‹‹ fluoxetine ‹‹ paroxetine ‹‹ quinidine ‹‹ ritonavir ‹‹ sertraline (>150 mg/d) ‹‹ TCAs

27. 2d6 No known inducers – possibly dexamethasone and/or rifampin

28. 1a2 Notable substrates ‹‹ caffeine (and theophylline ) ‹‹ clozapine ‹‹ cyclobenzaprine ‹‹ olanzapine ‹‹ probably several other typical antipsychotics

29. 1a2 Notable inhibitors ‹‹ caffeine ‹‹ cimetidine ‹‹ fluoroquinolones ‹‹ fluvoxamine ‹‹ grapefruit juice

30. 1a2 Notable inducers ‹‹Cruciferous vegetables (broccoli, brussels sprouts, cauliflower) ‹‹ carbamazepine ‹‹ modafinil ‹‹ rifampin ‹‹ TOBACCO smoking

31. 2c9 Notable substrates ‹‹ glipizide / glyburide ‹‹ phenytoin ‹‹ S- warfarin THC

32. 2c9 Notable inhibitors ‹‹ cimetidine ‹‹ fluconazole ‹‹ fluoxetine / fluvoxamine / paroxetine ‹‹ metronidazole ‹‹ modafinil ‹‹ ritonavir ‹‹ sulfamethoxazole ‹‹ valproate

33. 2c9 Notable inducers ‹‹ carbamazepine ‹‹ phenobarbital ‹‹ phenytoin ‹‹ rifampin

34. 2c19 Notable substrates ‹‹ diazepam ‹‹ phenytoin ‹‹ tertiary amine TCAs

35. 2c19 Notable inhibitors ‹‹ carbamazepine ‹‹ cimetidine ‹‹ disulfiram ‹‹ fluoxetine ‹‹ fluvoxamine ‹‹ omeprazole ‹‹ sertraline ‹‹ ritonavir ‹‹ topiramate

36. 2c19 Notable inducers (same as 2C9) ‹‹ carbamazepine ‹‹ phenobarbital ‹‹ phenytoin ‹‹ rifampin

37. 2e1 Notable substrates ‹‹ acetaminophen ‹‹ ethanol Notable inhibitors ‹‹ disulfiram ‹‹ isoniazid

38. 2e1 Notable inducers ‹‹ chronic ethanol use ‹‹ isoniazid ‹‹ obesity ‹‹ retinoids ‹‹ tobacco smoking

39. 2b6 Notable substrates ‹‹ bupropion ‹‹ cyclophosphamide / ifosfamide ‹‹ tamoxifen

40. 2b6 Notable inhibitors ‹‹ fluoxetine ‹‹ fluvoxamine ‹‹ nefazodone ‹‹ paroxetine ‹‹ sertraline

41. 2b6 Notable inducers ‹‹ phenobarbital ‹‹ phenytoin ‹‹ rifampin

42. Thank you