1. Drug metabolism Prof. M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Cycle II, Subject: General pharmacology Lecture: 14th November 2012 8:00-9:30, Burian Hall, Ruská 87, Prague Charles University in Prague, Third Faculty of Medicine

2. METABOLIC (biotransformation) mostly in the liver the drug is made more polar, hydrophilic – this increases its excretion in the urine PHASE 1 > PHASE 2 … ENZYME INDUCTION/ INHIBITION CYPs - cytochrom P450, microsomal enzymes, oxidases - GENE POLYMORPHISM EXCRETION mostly by the kidneys metabolites or unchanged GIT... enterohepatic circulation e.g. tetracyclines Lungs (volatile anaesthetics)

3. PHASE 1 REACTIONS OXIDATIONS are the most common reactions and these are catalysed by an important class of enzymes called microsomal enzymes or CYTOCHROME P-450 (CYP-P450) Other, relatively uncommon, Phase I reactions are reductions and hydrolysis

4. Downloaded from: StudentConsult (on 11 November 2012 11:34 AM) © 2005 Elsevier Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, this group then serves as the point for the conjugating system to attach a substituent such as glucuronide

5. Phase 2 reactions involve CONJUGATION (i.e. attachment of a substituent group), which usually results in inactive metabolites, occasionally in active metabolites (e.g. morphine- 6-glucuronide is an active metabolite of morphine) The groups most often attached are glucuronyl, sulfate, methyl and acetyl PHASE 2 REACTIONS

6. CYTOCHROM P-450 (CYP-450 s or CYP s ) Cytochrome P450 monooxygenase system, microsomal enzymes, microsomal oxydases 2/ The cytochrome P450 is a large group of enzymes that catalyze the oxidation of organic substances. 1/ CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism. 5/ There are many isoforms of CYPs, some with important individual differences in gene expression due to GENE POLYMORPHISM that may be of great importance in therapeutics. 4/ Activity of CYPs can be inhibited or increased by drugs (or other chemicals) - ENZYME INHIBITION/INDUCTION that may be of great importance in therapeutics. 3/ They contain a heme cofactor and, therefore, are hemoproteins

7. ENZYME INHIBITION (Inhibition of CYP-450, microsomal enzymes may cause adverse drug interactions (increased toxicity of drugs that are deactivated by the enzyme) rapidly occuring (after the 1st dose) e.g. clarithromycin (a macrolide antibiotic) may increases effects of warfarin (an anticoagulant) grapefruit juice may increase effects of calcium channel blockers (antihypertensives, antidysrhytmic drugs)

8. ENZYME INDUCTION (Induction of CYP-450, microsomal enzymes Repeated administration of some drugs increases (in 2-3 days) the synthesis of CYP-450 = enzyme induction may cause adverse drug interactions: mostly decreased effects of drugs that are deactivated by the enzyme e.g. rifampicin (anti-tuberculosis drug) reduces effects of sex hormones (oral contraceptives) or of warfarin (anticoagulant)

9. CYP3A4 CYP2D6 CYP2C9 There are many isoforms of CYPs CYP2C19 CYP3A4 is involved in the metabolism of about 50% of drugs. Gene polymorphism CYP 3A4 does not practically influence interindividual variability CYP2D6 shows the largest phenotypical variability among the CYPs, largely due to genetic polymorphism Genetic polymorphisme exists for CYP2C9 expression because the CYP2C9 gene is highly polymorphic. Some 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin

10. N-demethylation [ CYP3A4] nor-derivates O-demethylation [CYP2D6] codeine -> morphine oxycodone -> oxymorphone hydrocodone-> hydromorphone Glucuronidation * * [UGT] morphine -> morphine- 6-glucuronide [M6G] active metabolites: *[UGT] uridine diphosphate glucuronosyl transferase

11. (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride tramadol hydrochloride [tramadol – >demethyl tramadol (M1 metabolite)] O-demetylation [CYP2D6]

12. CYP 2D6 GENE POLYMORPHISM Ultrarapid metabolizers 2-3(7)% Poor metabolizers 7-10 % Rate Rapid +intermediate metabolizers No. of subjects Ultrarapid Metabolizers Ultrarapid metabolizers have extra copies of genes for CYP 2D6. They make more enzyme than normal. Ultrarapid metabolizers may break down some drugs (e.g. some antidepressants) so quickly that the drug does not need to help at usual doses. They may also need a lower dose of a drug, in the case where a drug is metabolized in active metabolites (e.g. in some opioid analgesics) Poor Metabolizers Poor metabolizers have variants of genes for CYP 2D6 that do not work normally. They make much less enzyme than normal or none at all. Poor metabolizers have a higher risk for side effects from some drugs (e.g. some antidepressants) and may need to avoid those drugs or take a lower dose. They may also need a higher dose of a drug, in the case where a drug is metabolized in active metabolites (e.g. in some opioid analgesics)