Pharmacokinetic Drug Interactions


Key Principles:


The clinical significance of a pharmacokinetic drug interaction is dependent upon the magnitude of the alterations and the steepness of the concentration-response relationship for the effected drug. It is important to recognize that the presence of a pharmacokinetic interaction does not necessarily require a change in the dosage regimen of the effected drug. Some drugs have a shallow concentration-response relationship, such that changing the drug concentration by 30% would not alter the clinical response to the drug. Others have a steep concentration response curve, such that small changes in the concentration of drug may result in significant changes in clinical response. Thus, the observation of a statistically significant pharmacokinetic interaction between two drugs in a group of normal volunteers should not be immediately translated as a clinically significant observation. In fact, while many drug interactions have been reported in normal volunteers, few studies have actually been conducted in patients to determine if the interaction is of clinical significance.


††††††††††† Clinically significant drug interactions necessitate alterations in drug regimen not only when an interacting drug is added to a patientís therapy, but also when an interacting drug is removed. While generally recognized that adding a drug to a patientís therapeutic regimen that significantly interacts with another drug, the regimen of the altered drug will need to be changed, it is sometimes forgotten that the removal of the interacting drug also necessitates a change in the dosage regimen of the impacted drug. For example, if a patient who is receiving methyldopa has ferrous sulfate added to their regimen, the absorption of methyldopa will be reduced. To compensate for this, the dose of methyldopa may be increased. If at a later point in time the ferrous sulfate is removed from the patientís regimen, the dose of methyldopa would need to be decreased, otherwise the concentrations of the latter would increase and may result in toxicity.


††††††††††† The most significant pharmacokinetic drug interactions are generally those involving alterations in the metabolism of a drug subjected to significant first-pass metabolism after oral administration. The reason this is true is that it is in these situations the alteration in drug concentrations is the greatest. For example, if a drug that is subject to first-pass metabolism has a systemic availability of 1%, that means 99% is metabolized through first-pass metabolism.If we add an inhibitor that reduces the fraction metabolized to 95%, the systemic availability is now 5% - a 5-fold increase in the amount of drug that enters the systemic circulation. This will result in a substantial increase in the peak concentration of drug, as well as the average steady-state concentration.


††††††††††† While drug displacement interactions are common, they rarely result in clinically significant changes in drug response. It is relatively easy to demonstrate drug displacement interactions in vitro. As a result, you will find many reports of one drug displacing another drug from plasma protein binding sites. Usually, however, such changes in the free fraction of a drug do not result in significant changes in the free drug concentration. The only situation where this does occur is when a displacement interaction occurs with a drug that exhibits a high clearance (approaching hepatic blood flow) is administered intravenously. In this situation, a displacement from plasma protein binding sites may result in clinically significant increases in the free drug concentration. For other circumstances (oral or intravenous administration of a drug with a low clearance or administration of a drug with a high clearance orally), there will be a change in the total drug concentration, but not in the free concentration. For this reason, measurement of total drug concentrations can be misleading and result in inadvisable recommendations for changes in the drug dosage regimen.



Practice Problems:


1.      Sumatriptan is an agent used in the acute treatment of migraine headaches. It is available for both oral and subcutaneous administration. The average total clearance of sumatriptan is approximately 19 mL/min/kg, while the volume of distribution is 0.65 L/kg. An average of 22% of the drug is excreted unchanged in the urine, while the rest is metabolized hepatically. Based on these pharmacokinetic characteristics, indicate whether concurrent administration of an inducer of sumatriptan metabolism would be expected to increase, decrease, or not change the following pharmacokinetic parameters compared to administration of sumatriptan alone.


AUCoral:††††††††††††††† CLH:††††††††††††††† t1/2:†††††††††††††††† Cmax after oral administration:†††††††††††††††††††††††††††††††††††† Vss:†††




2.      TM is a 56 yo male who is admitted to the coronary care unit with a suspected myocardial infarction. Because TM exhibited excessive PVCs on his electrocardiogram, he was administered a loading dose of lidocaine and placed on a constant infusion the drug. Forty-eight hours after the initiation of the lidocaine infusion, TM experienced several episodes of mild chest pain. In response, propranolol 40 mg q 6 hr po is added to this patientís drug regimen. Among its effects, propranolol displays negative inotropic activity. What impact would you expect the addition of propranolol to have on the clearance and steady-state concentrations of lidocaine? Based on this impact, what recommendations would you make regarding this patients therapeutic regimen. Answer





Last revised 07/13/05


2005 - Craig K. Svensson, Pharm.D., Ph.D.


Return to the Index for Lecture Tutorials


Return to Pharmacokinetics and Biopharmaceutics Homepage