Inhibition and induction of drug metabolism

Description on inhibition and induction of drug metabolism

1. INHIBITION AND INDUCTION OF
DRUG METABOLISM
Dr.Ramesh Bhandari
Asst. Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. INHIBITION OF DRUG METABOLISM
Thephenomenonofdecreaseddrugmetabolizingabilityof
theenzymesbyseveraldrugsandchemicalsiscalledas
enzymeinhibition.
Theprocessofinhibitionmaybeoftwotypes:
1)DirectInhibition
2)IndirectInhibition

3. DIRECT INHIBITION
It may result from the interaction of enzyme site, the outcome being a change in
enzyme activity, direct inhibition can occur by one of the three mechanisms.
A.Direct Inhibition:
1.Competitive Inhibition: Eg: Methacholinecompetes with Ach of choline esterase.
2.Non-Competitive Inhibition: Eg: INH inhibits Phenytoin Metabolism.
3.Product Inhibition
B.Indirect Inhibition:
1.Repression
2.Altered Physiology

4. EXAMPLES OF ENZYME INHIBITION:
i.Fluvoxaminedoublesthehalflifeofdiazepam
ii.QuinidineinhibitsthemetabolismofNifedipineorother
calciumchannelblockingagents.
iii.TheophyllineclearanceisdecreasedbyCimetidine.
iv.Interferonreducesmetabolismoftheophylline.
v.CimetidineandDiazepaminteraction.

5. INHIBITION OF MONO AMINE OXIDASE (MAOs)
Non-hepaticenzymescanbeinvolvedindruginteractions.
Linezolidwithserotonergicpsychiatricmedicationslike
antidepressantsuchascitalopram,paroxetine,fluoxetineand
sertralineandotherdrugswhichaffectstheserotonergicpathwayin
thebraincancauseserotoninsyndrome.
LinezolidisareversibleMonoAmineOxidaseInhibitor.
MonoAmineOxidaseisresponsibleforbreakdownofserotoninin
thebrain.
IfMAOIandlinezolidisgivenconcurrentlytheserotoninlevelwill
increaseswhichwillleadtoserotoninsyndrome.

6. INDUCTION OF DRUG METABOLISM
Thephenomenonofincreaseddrugmetabolizing
abilityoftheenzymesbyseveraldrugsand
chemicalsisknownasenzymeinduction.
CytochromeP-450isozymesareofteninvolvedinthe
metabolicoxidationofmanydrugs.
Manydrugscanstimulatetheproductionofhepatic
enzymes.

7. Examples of Induction of Drug Metabolism:
Therapeuticdosesofphenobarbitalandotherbarbiturates
acceleratethemetabolismofcoumarinanticoagulantssuch
aswarfarinandsubstantiallyreducethe
hypoprothrombinemiceffect.
Otherdrugsknowntoinducedrugmetabolisminclude
carbamazepine,rifampin,valproicacid,andphenytoin.
Enzymaticstimulationcanshortentheeliminationhalf-life
oftheaffecteddrug.Forexample,phenobarbitalcanresult
inlowerlevelsofdexamethasoneinasthmaticpatients
takingbothdrugs.

8. INHIBITION
OF
BILIARY SECRETION

9. INHIBITION OF BILIARY EXCRETION
Amongalltherouteofdrugexcretion,Bileisalsooneofthem.
Drugsareoftenconjugatedwithbileandthenexcretedfromthebodyin
bile.
Watersolubledrugsandmolecularweightgreaterthan300Dare
largelyexcretedinbile.
ExcretionofdrugsinbileismainlyviatransporterssuchasMDR1(P-
glycoprotein),MRP1,MRP2,MRP3etc.
Hencethereispossibilityofdruginteractionifdrugsaregiven
concomitantlywithotherdrugsbyaffectingAUCorbioavailabilityof
unchangeddrug.

10. Drug conjugates with glucuronides and then excreted in bile
Excreted in duodenum in the small intestine
Bacteria in the intestinal tract deconjugatesinto free form of drug
Absorbed again from the small intestine into the enterohepatic circulation

11. HEPATOBILIARY DRUG INTERACTION
Theco-administrationofdrugswhichinhibitstheco-
transporterinvolvedinbiliaryexcretionofdrugwhichare
substratesofthetransporter,leadingtoelevatedplasma
drugconcentration.
Eg:Biliaryexcretionofdigoxinismediatedby
P-glycoproteinwhichareinhibitedbyQuinidine.Hence
bothdigoxinandquinidineisgivenconcomitantlydigoxin
levelswillincreaseandmayshowadverseeffect.

12. OtherinhibitorsofP-GlycoproteinareVerapamiland
cyclosporinewhichactsbydifferentmechanisms.
VerapamilisacompetitiveinhibitorofthisP-glycoprotein
whereascyclosporineinhibittransportfunctionby
interferingwithsubstraterecognitionandATPhydrolysis.
InhibitionofP-Glycoproteinresultsindecreasein
clearanceofdrugandleadtoincreaseindruglevelswhich
maycausetoxicity.
Eg:Verapamilincreasessteadystateplasmaconcentrationof
Digoxinduetoinhibitionofbiliaryexcretionofdigoxin.