NADPH- Cyt. P450 reductase P450 S SOH O 2 H 2 O e NADPH NADP +

Aromatic hydroxylation

Aliphatic hydroxylation

Epoxidation

Dealkylation

CYP1A Metabolize polycyclic hydrocarbons Are induced by polycyclic hydrocarbons –Found in cigarette smoke –Associated with cancer CYP1A1 –is inducible –extrahepatic CYP1A2 –is constitutively expressed only in liver –Is inducible

CYP1A Polymorphisms (primarily CYP1A1) –Expression polymorphism –Structural gene polymorphism In vivo assay (CYP1A2) –Caffeine metabolism

CYP 2A CYP2A6 and CYP2A13 –CYP2A6 is polymorphic –Responsible for nicotine metabolism CYP 2B CYP2B6 – CYP2B1 and CYP2B2 are major forms in rats –was originally thought to be a minor form in humans

CYP2C CYP2C8, CYP2C9, CYP2C18, and CYP2C19 are major forms in humans Hormonally regulated in rodents (growth hormone) Metabolize about 30% of commonly used drugs –Omeprazole –Diazepam In vivo substrates –S-mephenytoin (CYP2C19) –Flurbiprofen (CYP2C9)

CYP2D6 Metabolize many important drugs –Codeine –Dextromethorphan Polymorphisms –Mutation in the structural gene –Related to increased cancer risk (rapid metabolizers) In vivo substrate –Debrisoquine –Dextromethorphan

CYP2E1 Is uncoupled –Produces superoxide and hydrogen peroxide Forms reactive intermediates –Nitrosamine carcinogens –acetaminophen

CYP2E1 Is uncoupled Forms reactive intermediates –Associated with acetaminophen toxicity Ethanol inducible Polymorphisms –Linked to cancer –Role in alcohol-related liver dysfunction In vivo substrate –chlorzoxazone

CYP3A4/5 Major P450 in humans - metabolizes over 50% of commonly used drugs Is inducible by numerous drugs CYP3A4 not polymorphic – but wide variation in activity (due to CYP3A5) In vivo substrates (hepatic and intestinal) –Erythromycin –Alfentanil

Hydrolysis reactions Plasma, liver, kidney, and all tissues Esterase –Succinylcholine apnea Amidase Epoxide hydrolase –Found in liver and all tissues –Both microsomal and soluble forms –Inducible by phenobarbital and 3- methylcholanthrene

Hydrolysis reactions Esterase (plasma, liver, and kidney) –Succinylcholine apnea Amidase (liver) Epoxide hydrolase –Found in liver and all tissues –Both microsomal and soluble forms –Inducible by phenobarbital and 3- methylcholanthrene

Hydrolysis reactions Esterase (plasma, liver, and kidney) –Succinylcholine apnea Amidase (liver) Epoxide hydrolase –Found in liver and all tissues –Both microsomal and soluble forms –Inducible by phenobarbital and 3- methylcholanthrene

Conjugations reactions (phase 2) Glucuronidation Sulfate conjugation Acetylation Glutathione conjugation Methylation Glycine conjugation

Acetylation N-acetyl transferase

Glutathione conjugation

Methylation Methytransferases Cytoplasm and endoplasmic reticulum S-adenosymethionine Amino acid conjugation Usually as glycine conjugates Mitochonria and cytoplasm

elimination A A absorption Total Body Volume A

distribution Central compartment A A AA absorptionelimination

One Compartment Model Intravascular Bolus

One Compartment Model Extravascular

Two Compartment Model Intravascular Bolus

Two Compartment Model Extravascular

Apparent Volume of Distribution

Continuous IV Infusion

Multiple IV Administration

Multiple Extravascular Administration