435-bioavailability 2

extraction ratio (E)

fraction of drug eliminated by a drug-eliminating organ during single pass

values range 0-1

drug dependent

organ CL = Q x E

volume of plasma from which a drug is completely cleared by a drug-eliminating organ per unit of time (Q x E)

Q = blood flow

high E drug

inc Q = inc organ CL

low E drug

inc Q = no change

CLh = Eh x Qh

high E drugs: Eh greater than 0.7

low E drugs: Eh less than 0.3

if Eh = 1, then CLh approaches Qh

Eh = CLh / Qh

this will tell us if high E drug or low E drug

high Eh drugs #

Eh greater than 0.7 (remove a large portion of the drug)

low Eh drugs #

Eh less than 0.3 (remove a small portion of the drug)

low Eh drug ex

theophylline, warfarin

high Eh drug ex

verapamil

high Eh drugs

already good substrates for hepatic metabolism; mainly depend on Qh (blood flow)

low Eh drugs

poor substrates for hepatic metabolism; depend on protein binding + enzyme capacity

high F bc not much of drug is lost in the first place

CL intrinsic

liver’s built in ability to remove a drug if it had full access to it [independent of blood and protein binding]

large CL int

drugs that are good substrates/rapidly metabolized by liver in unbound form

small CL int

drugs that are poor substrates/take a long time to be metabolized in unbound form

CLint = Vmax / Km

can only be estimated in vitro studies

enzyme inducers..

inc CLint [ex: phenobarbital + rifampin]

enzyme inhibitors..

dec CLint [ex: erythromycin + cimetidine]

low Eh drug eq

CLh = Fu x CLint

high Eh drug eq

CLh = Qh

factors that affect Qh

disease states (dec)

food (inc)

factors that affect CLint

liver disease states, enzyme inhibitors (dec)

enzyme inducers, cigarettes (inc)

factors affecting fu

liver disease states (dec circulating plasma proteins)

factors affecting CLh

fu

Qh

CLint

low Eh characteristics

only affected by changes in CLint + fu

high Eh characteristics

only affected by changes in Qh