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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. 1 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. 2 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. 3 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. 4 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 5 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. 6 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. 7 - 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. 8