Download المحاضره الثامنه Effect of changing intrinsic clearance and or blood

‫المحاضره الثامنه‬
 Effect of changing intrinsic clearance and or blood flow on
hepatic extraction and elimination half life after IV and oral
dosing.
 The changes in intrinsic clearance and blood flow affect the elimination
half-life, first –pass effects and bioavailability of the drug.
Effect of changing intrinsic clearance:
1- For drugs with low ER, the effect of doubling CLint
increase both the
ER and clearance (CL)
Shorter t1/2, ( i.e. the elimination half-life decreases
about 50 % due to increase in CLint ).
- This means that, there is a decrease in both AUC and t1/2 due to increase in
clearance of drug after oral administration.
2- For drugs with high ER, the effect of doubling CLint
increase both ER and
clearance only moderately
elimination half life decreases only
moderately also some decrease in AUC
and t1\2 is shortened moderately.
1- The elimination half life of a drug with low extraction ratio is decreased
significantly by an increase in hepatic enzyme activity (intrinsic clearance).
2- In contrast the elimination half-life of a drug with high ER is not markedly
affected by an increase in hepatic enzyme activity because enzyme activity
is already quite high.
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Effect of changing protein binding on hepatic clearance:
- Protein –bound drugs are not easily metabolized (restrictive clearance) while
free (unbound) drugs are subject to metabolism.
- Drug protein binding is not a factor in hepatic clearance for drugs that have
high extraction ratios (ER). These drugs are considered to be flow limited.
- In contrast, drugs that have low ER may be affected by plasma protein
binding depending on the fraction of drug bound.
1- For a drug that has a low extraction ratio and less than 80% bound
changes in protein binding will not produce significant changes in CLh.
small
2- Drugs that are highly bound to plasma protein but with low ER are considered
binding sensitive because
small displacement in protein binding will cause
a very large increase in free drug conc.
- The large increase in free drug conc. will cause
metabolism
increase CLh.
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increase in rate of
For a drug with restrictive clearance, the relationship of blood flow,
intrinsic clearance and protein binding is:
CL h = Q (fu Clint1 / Q +fu CLint1 )
Where:
fu: fraction of drug unbound in blood.
CLint1 : intrinsic clearance of free drug
- When the CLint1 is very small in comparison to hepatic blood flow (i.e. Q > CLint 1).
CLh =Q fu CLint1 / Q
- A change in CLint1 or fu will cause a proportional change in CLh for drugs with
protein binding.
Drug interactions involving drug metabolism:
- Enzymes involved in the metabolism of drug may be altered by:
1-Diet
2- Co-administration of the drugs and chemicals.
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Enzyme induction:
- It is a drug or chemical stimulated increase in enzyme activity, due to an increase
in the amount of enzyme present.
Agents that induce enzymes include.
1- Aromatic hydrocarbons (such as benzobyrene found in cigarette smoke)
2- Drugs such as:
- Carbamazepine, phenytoin, rifampin, valproic acid Phenobarbital.
For example:
- Therapeutic dose of Phenobarbital and other barbiturates accelerate the
metabolism of warfarin (anticoagulant).
- Fatal hemorrhagic episodes can result when Phenobarbital is withdrawn and
Warfarin dosage maintained at its previous level.
- Enzymatic stimulation can shorten the elimination half-life of the affected
drug.
Phenobarbital can result in lower levels of dexamethasone in asthmatic patients
taking both drugs.
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Enzyme inhibition:
- May be due to substrate competition or due to direct inhibition of drug
metabolizing enzyme.
- Fluoxetin causes a ten - fold decrease in the clearance of imipramine and
desipramine because it is inhibitory affect on hydroxylation (metabolism).
Pharmacokinetics drug interaction involving hepatic elimination:
1- Enzyme induction:
- Smoking (polycyclic aromatic hydrocarbons)
clearance
- Barbiturates
increase theophylline
Phenobarbital increases the metabolism of warfarin.
2- Enzyme inhibition:
- Cimetidine
metabolism.
decrease theophylline and decrease diazepam
- Fluvoxamine
longer diazepam t1/2
- Quinidine
decrease nifedipene metabolism
- Fluconazole
metabolism).
increase levels of phenytoin and warfarin (decrease
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 Warfarin & phenobarbital:
- Phenobarbital by causing enzyme induction
warfarin
response to anticoagulant
formation if the interaction is not recognized.
rate of metabolism of
risk of thrombus
- Benzodiazepines (diazepam, valium) are not interacting with
anticoagulants; so one of these agents might be used as an alternative to a
barbiturate.
 Inhibition of drug metabolizing enzymes:
- Interactions between drugs that lead to impaired metabolism are more
important than those that result from stimulated metabolism (why) ?
- Because: the clinical consequence of enzyme induction is
decrease in
the efficacy of the drug (this is undesirable but rarely life-threatening).
- Inhibition of drug metabolism
accumulation of drugs to toxic levels.
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serious adverse effects because of
 Enzyme inhibition often results in exaggerated & prolonged response
rise of toxicity.
 These drugs have the capacity to inhibit the hepatic enzymes usually by
competitive binding to hepatic enzymes & form stable complex
prevents access of other agents to hepatic enzyme system.
 Enzyme inhibition appears to be a dose related phenomenon
(why)?
- Inhibition of metabolism of the affected drug begins as soon as the sufficient
conc. of the inhibitor appears in liver & the effects are maximal when the
steady – state plasma conc. is achieved.
 The clinical significance of this type of interactions (enzyme
inhibition ) depend on various factors :
1- Dosage (of both drugs).
2- Alterations in pharmacokinetic properties of the affected drug such as a
prolonged half- life & patient characteristics such as disease state.
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- Interactions of this type affects on drugs with narrow therapeutic range such as
theophylline.
For example:
- The introduction of an enzyme inhibitor such as ciprofloxacin or cimetidine in
patient taking chronic theophylline
doubling of plasma concentrations
of theophylline.
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