Metabolism

METABOLISM OF DRUGS

BIOTRANSFORMATION

PURPOSE• Major Purpose:- Make the drug inactive…less toxic- Remove it out of the bodyHow it is achieved?- Phase 1 metabolism: inactivate….less souble.- Phase 2: least soluble in lipid….excretableHow reducing lipid solubility helps in excretion?- Glomerular filtration, tubular reabsorption…

lipid soluble drugs diffuse back to blood across tubular epithelium. Water soluble can not!

What exactly happens in phase 1 & 2?• Phase 1….chemical modification- Oxidation- Reduction- HydrolysisPhase 2….conjugation with a polar group makes it less lipid

soluble- Glucuronide conjugation- Glycine conjugation- Glutathione conjugation- Acetylation- Methylation- Sulfation

What is first pass metabolism?• The amount of drug metabolised in its first

passage from site of administration to circulation• What is the importance of first pass

metabolism?The amount of first pass metabolism determines

the bioavailability of drug.Nitoglycerin has extensive first pass metabolism

and it can be avoided by giving sublingually.Lignocaine has extensive first pass metabolism and

it has to be given intravenously

First pass contd…

• Morphine high first pass…usually given parenterally.

• Propranolol high first pass in liver. CCF blood supply to liver reduced….metabolism less…more concentration…..same with liver disease….reduce dose.

• Peptides inactivated by proteolysis in git. Parenterally.

prodrug• Inactive themselves…become active after

undergoing metabolism.• LDOPA…- Designed with a purpose in mind.- Dopamine…parkinsonism…BBB…- LDOPA crosses BBB. Converted to dopamine. Esters..hydrolysis…parent drugBacampicillin, talampicillin…to ampicillinBetter absorbed …better bioavailability…lesser

frequency….better patient complianceLesser GI adverse effects…super infection, diarrhoea

Prodrug….

• Metronidazole Benzoylate…. Metronidazole base is unpalatable. Paediatric patient…poor acceptance. Benzoylate is taste less…ester..

• Erthromycin base bitter …..esters bland• Mandelamine (methenamine mandelate)

….formaldehyde….acidic pH…renal tubules…formalin itself fixes cells! Urinary infection…urinary antiseptic.

Synthetic reactions (Phase 2)(conjugation) Non synthetic reactions (phase 1)

Type of reaction Determined by functional group Determined by functional groupLimited number Wide varietyRelatively predictable Relatively unpredictable

Metabolite Almost always less lipid-soluble Usually less lipid-solubleAlmost always pharmacologicallyinactive May have less, equal, greater or

different activityReactions catalyzed byNon microsomal enzymes

All except glucuronideconjugation Most hydrolyses; some

oxidations and reductionsNo stimulation of rate ofbiotransformation by other drugs No stimulation of rate of

biotransformation by other drugsReactions catalyzed bymicrosomal enzymes

Only glucuronide conjugation Most oxidations and reductions;Some hydrolyses

Rate of reaction stimulated bydrugs Rate of reactions stimulated by

many agents

Cyp450? superfamily• P450s are highly abundant in liver cells.• Reddish brown….heme; hemoproteins• Mcicrosomes ( vesicles)• Endoplasmic reticulum.• Separate out at a centrifuge speed of 100000g.• CYP is a diverse group of enzymes that catalyze

the oxidation of organic substances. • substrates include metabolic intermediates such

as lipids and steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals.

• account 75% metabolic reactions.

Cyp450? Superfamily……….

• P450 = spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with CO.

• Based on the nature of the electron transfer proteins CYPs can be classified into several groups

- Microsomal P450 systems- Mitochondrial P450 systems- Bacterial P450 systems- P450 only systems; CYP5 (thromboxane

synthase), CYP8 (prostacyclin synthase), and CYP74A (allene oxide synthase).

Nomenclature• Genes encoding CYP enzymes, and the enzymes

themselves, are designated with the abbreviation CYP followed by a number indicating the gene family, a capital letter indicating the subfamily, and another numeral for the individual gene.

• Italicise the name when referring to the gene.• Cyp 3A4 = enzyme• Cyp 3A4 = gene• 3 = gene family, A= subfamily, 4 = individual gene• The Human Genome Project has identified 57

human genes coding for the various cytochrome P450 enzymes.

CYP…..• The most common reaction catalyzed by

cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:RH + O2 + NADPH + H+ → ROH + H2O + NADP+

• CYP Enzyme inducers• CYP Enzyme inhibitors• DRUG INTERACTIONS affect metabolism &

clearance of various drugs

Various enzymes involved in metabolism of drugs

Examples of Substrates, Inhibitors and Inducers of CYPs

Enzyme inducers

• Phenobarbitone• Phenytoin• Carbamazepine• Rifampicin• Alcohol• Tobacco smoke• Marijuana smoke• Onset 2 days, peak 2-3 weeks, increase in

smooth endoplasmic reticulum

• Rifampicin- Auto induction- Warfarin- Oral contraceptives• Phenobarbitone- Warfarin ….stabilised on phenobarb, if

phenobarb withdrawn, fatal hemorrhage.- Oral contraceptives

Enzyme induction….

• Phenytoin- Warfarin- Theophylline• Carbamazepine- Auto induction- Warfarin- But inhibits phenytoin metabolism• Smoking- Theophylline- Imipramine- Pentazocin- propranolol

Enzyme induction….

• ETHANOL- Chronic alcoholism, liver disease, abnormal

drug metabolism- Acute ethanol administration…inhibit …

competition Inhibit NADPH cytochrome P-450 reductase,

the rate limiting step in the oxidative biotransformation of drugs; higher plasma levels of many benzodiazepines;

also inhibit phase two reactions.

Enzyme induction….

• chronic ethanol intake enhances the rate of drug metabolism; increase in microsomal mass.

- Phenytoin- Phenobarbitone- WarfarinWithdrawal of alcohol may cause drug

interaction.Food: a low protein diet, diminished NADPH

dependent enzymes. High carb diet…low microsomal MFO activity.

Enzyme induction….

• Crigler-Najjar syndrome type II and Gilbert's syndrome; unconjugated hyperbilirubinemia; reduction in the activity of glucuronyl transferase; jaundice; phenobarbitone; increased glucuronyl tranferase, incresed blood flow, increased bile flow.

• Phenobarbitone, phenytoin; long term; epilepsy; increased vit D inactivation, osteomalacia,