Drug Interactions in Patients

• Goals:
– Understand factors causing variation between individuals in dose-response
– Know how to adjust dose to allow for these factors and bring response to desired intensity of effect.
Questions to ask when someone responds inappropriately to a drug, measure the plasma drug level.
Is it PK or tissue sensitivity problem?
Ask:
Is the effect in accordance with the plasma concentration?
Or
Is the concentration appropriate for the dose?

Faster the stomach empties, the higher the peak dose

Drugs that affect gastric emptying: propantheline delays, metaclopramide accelerates gastric emptying
Most severe trauma and acute illness will delay gastric emptying. (also migraines)

An effect of food on bioavailability as measured by AUC:

Is the drug lipid soluble? Then taking it fed increases AUC, but for many drugs it doesn’t matter.

Cholesterol resins will reduce absorbtion of anionic compounds  Ion exchange resin and anion
drug absorption
Changing stomach pH (antacids) may affect absorption

ABC transporters
– Use ATP hydrolysis for energy to move molecules that go slowly if at all by diffusion
– Ex. BBB is ABC transporters (p-glycoprotein & others) in endothelial cells that pump out HIV
PIs and NRTIs. These transporters are induced by HIV infection.

• BBB keeps antineoplastic drugs out of CNS. Attempts to improve the

response of metastases in the brain to chemotherapy by giving drugs
which slow these transporters have been disappointing so far.

Phenobarbital induces estrogen-degrading enzymes; same for rifampin

Smoking and theophilline

Patient with meningitis showing inhibition of phenytoin by

chloramphenicol (so drug levels go up)

Oxidation of felodipine due to CYP3A4 in small bowel

Grapefruit juice: was originally a study seeking to show drug interactions
with alcohol (vodka) but mixed with grapfruit juice instead of OJ:

Is it P450 eliminated? Then suspect P450 induction as a culprit for

changing dose-response relationship.

Clipidogrel and Omeprazole

• Clipidogrel is metabolized to an active
metabolite by CYP 2C19. This metabolite, not
Clipidogrel, blocks platelet activation.
• Desired effect to prevent stent thrombosis.
• Undesired effect of increased risk of GI
bleeding.
• A number of drugs are inhibitors of this
enzyme.

Inhibitors of CYP 2C19

PPIs:
lansoprazole
omeprazole
pantoprazole
rabeprazole
chloramphenicol
cimetidine
felbamate
fluoxetine
fluvoxamine
indomethacin
ketoconazole
modafinil
oxcarbazepine
probenicid
ticlopidine
topiramate
So taking a PPI can make your anti-platelet drug less effective.

But this study shows the opposite outcome: because the PPIs were different!

Drug Excretion Interactions

• Nonionic back diffusion
– Waddell and Butler, JCI, 1957
• Competition for tubular secretory pathways

increasing rate of urine flow increases rate of excretion of

Phenobarbital.
Also showed that if you give NaBicarb to alkanize the urine, you get much higher clearance at any given urine flow. Phenobarb
is an organic acid, so it can be present as either unionized acid or as the anion. Unionized acid will be reabsorbed. Concentration
gradient favoring reabsorbtion of unionized free acid. (not anion.) Only undissociated free acid concentration gradient counts.
Amphetamines are cations. Alkaline urine 
slow excretion.
Acidic urine promotes excretion.