Lecture 5: Hepatic Elimination Flashcards
Hepatic elimination consists of
-metabolism
-bilary excretion
Enterohepatic cycle
-small intestine to portal vein to liver to bile duct to small intestine
portal vein
-blood flow INTO liver
First-pass effect / presystemic elimination
-100% of oral drug goes to liver
-if 90% eliminated by liver, only 10% of drug gets to systemic circulation
Drug passage through liver
-drug enters liver lobule from portal vein through sinusoids
-blood flow from outside to inside
-drug enter space of disse
-diffusion or active transport to hepatocytes
lobule
functional unit of live
endothelium of sinusoid
-very porous
-drug diffuses into space of disse into hepatocytes
-then excreted in bile or goes to blood
Collection of bile
-hepatocytes secrete bile into canaliculi
-canaliculi converge to form small bile ductules and ducts
-bile moves from INside to OUTside of lobule
Passage from liver to intestine
-bile moves via hepatic ducts to gall bladder
-bile stored in gall bladder
-bile released in intervals into intestine (after meals)
No gall bladder
-bile always flowing into intestine instead of stored
-have to eat less fat
transporter proteins
-important for uptake and efflux form blood and transfer to bile
-pgp
-active transport
Greatest effect on billary excretion
-molecular weight
-optimal is 500-600 but >300
-low molecular wight can be passively absorbed before entering bile duct
-conjugated drugs more easily excreted
Conjugated drugs
-larger
-more readily excreted by bile
Classification of agents
-compounds that enter bile can be classified into 3 groups dependent on bile to plasma concentration
Class A compounds
-bile:plasma = 1
-Na+, K+, glucose
Class B compounds
-bile:plasma > 1
-bile salts, bilirubin, xenobiotics
-REQUIRE ACTIVE TRANSPORT INTO BILE
Class C compounds
-bile:plasma < 1
-insulin, phospholipids, sucrose, proteins
Enterohepatic circulation
- Systemic circulation -> liver
- Liver -> back to circulation or bile duct
- Bile duct –> GI tract
- GI tract –> portal vein to liver if it can be reabsorbed
Enterohepatic circulation
-can reduce elimination of xenobiotics
-drug can keep getting reabsorbed and stay in body longer
Interuption of enterohepatic cycling
-reduces half-life
-drug interactions can occur in GI tract
Dapsone
-20 hour half life
-add charcoal = drug coming from bile duct binds to charcoal in GI tract
-cant be reabsorbed
-shorter half-life
Bile binding agent
-increases elimination
-prevents enterhepatic recycling
drug storage in gallbladder
-periodic dose dumping into intestines
-can cause a spike in plasma concentration from reabsorption
Metabolite of drug in enterohepatic circulation
-drug broken down to metabolite in liver
-metabolite go back to GI tract through bile
-metabolite can be metabolized BACK into drug and go back to liver
Glucuronosyltransferase
-adds sugar to drug in LIVER
= glucuronide
glucuronidase
-removes sugar from glucuronide in GI TRACT
= back to drug
CPT-11 metabolism
-metabolized to SN-38G
-goes to GI tract
-cleaves G in intestine
=toxicity to bowels
neomycin
-decreases diarrhea from neomycin
-sterilize gut of microflora that produce glucuronidase
Pulmonary excretion
-only passive diffusion
-anesthetics or alcohol
blood:alveolar air ethanol
-constant ratio of 2100:1
-allows calculation of blood alcohol concentration
Hair excretion
-trace amounts of drug from circulation
-can estimate drug and metal exposure but NOT concentration
Detection time of drug tests (shortest to longest)
-saliva
-urine
-sweat
-meconium
-hair
Sweat and saliva excretion
-may cause skin reactions
milk excretion
-milk more acidic than plasma
-basic compounds may accumulate
-may pass agricultural compounds/antibiotics
Tear excretion
-rifampin stains contacts
Variability of drug response
-concentration that’s affected by elimination that’s affected by metabolism
variability in drug concentration
-ELIMINATION
-distribution and absorption
Variability in elimination
-METABOLISM
-bilary and renal excretion
Variability in metabolism
-genetics
-environmental exposure
-physiological variations
-disease
