Download Pharmacokinetic drug interaction

Mosul University College of pharmacy
Lab 2
Biopharmaceutics
Pharmacokinetic drug interaction
Drug interaction arc an avoidable cause of patient harm. Harm may occur due to
either increase drug effect causing toxicity or decrease drug effect leading to
therapeutic failure.
Software checkers for drug interaction are widely available, but have limited
clinical utility.
Patient harm from drug interactions can be reduced by:
•• using a personal formulary - using few drugs and knowing them well
•• recognizing drugs that are major perpetrators of interaction
•• recognizing narrow therapeutic index drugs as vulnerable to interactions
•• applying clinical pharmacology principles
Common narrow therapeutic index drugs:
 Amiodarone, theophylline
 Anticoagulants: warfarin
 Antiepileptics: phenytoin
 Aminoglycoside antibiotics: gentamicin
 Immunosuppressants: tacrolimus
Pharmacokinetic interactions are more complicated and difficult to predict because
the interacting drugs often have unrelated actions; the interactions are mainly due
to alteration of absorption, distribution, metabolism, or excretion, which changes
the amount and duration of a drug's availability at receptor sites.
Alteration of Gastrointestinal Absorption
There are three areas in which interactions might occur at the level of drug
absorption. One drug may affect the rate and/or extent of absorption of other drugs
if it alters: 1) GI motility, 2) gastric pH or 3) chemically binds with other drugs to
form insoluble, no absorbable complexes.
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Gastric pH: Ketoconazole and itraconazole, cefpodoxime, are weak bases,
virtually insoluble in water, and are ionized only at a low pH. Consequently,
dissolution and absorption of these compounds is heavily dependent on acidic
gastric conditions in the stomach ,Drugs that increase gastric pH (e.g.,H2
antagonists, proton pump inhibitors) slow the dissolution of the solid dosage forms
and decrease drug available for absorption in the gastric lumen.
GIT motility: Drugs that increase gastric emptying or intestinal motility, such as
erythromycin or metoclopramide, may hasten the passage of drugs through the GI
tract ultimately reduce total bioavailability, or area under curve (AUC). On the
other hand, such drugs as the opioids or anticholinergic that can decrease GI
motility may either reduce absorption by retarding dissolution and slowing gastric
emptying, or increase absorption by keeping a drug for a longer period of time in
the area of optimal absorption. Finally, in cases of either increased or decreased GI
motility, enteric-coated and sustained-release formulations that rely oil normal pH
gradients or residence times in the gut also may be affected.
Complexation and adsorption: Tetracycline, fluoroquinolones, levothyroxine and
the bisphosphonates can combine, or "chelate," with certain divalent ions (e.g., Ca,
Mg, Al, Fe and Zn) in the GI tract to form poorly absorbable complexes. Thus,
certain foods (e.g, milk) or drugs (e.g, antacids; products containing Mg, Al, and
Ca salts; or Fe preparations) can significantly decrease the absorption of those
drugs and in some cases lead to treatment failure. Even multivitamin preparations
that contain lower concentrations of minerals should be avoided. Similar adverse
effects on fluoroquinolone absorption were observed with concomitant
administration of ferrous sulfate, with decreases in bioavailability of the antibiotic
Antacids markedly reduce the absorption of fluoroquinolone derivatives (e.g.,
ciprofloxacin), probably as a result of the metal ions complexing with the drug.
Antacids should not be used simultaneously or <2 h after ciprofloxacin. The actual
influence of dairy products on fluoroquinolone absorption varies.
Complex formation through the process of adsorption also may occur with the bileacid sequestrants (e.g, cholestyramine and colestipol). In addition to binding with
and preventing reabsorption of bile acids, these agents can bind with certain drugs
in the GI tract and reduce their systemic bioavailability"
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The binding resins have the greatest affinity for acidic drugs, including thyroid
hormones, warfarin, propranolol, tetracycline, esrtogens and progestins, digoxin
and other. They also may bind to fat-soluble vitamins, such as vitamin A, Vitamin
D, Vitamin E and Vitamin K.
Distribution: Competition for protein binding, in particular with serum albumin is
another potential source of drug interactions. Although this type of interaction has
increasingly come under fire as having little clinical significance, for drugs that are
very highly bound (greater than 90%) and have a narrow therapeutic index, the
possibility of clinically significant interactions does increase. Furthermore, these
types of interactions may be more likely to occur in those with hypoalbuminemia
often seen in the elderly, malnourished, patients with liver disease or chronic
alcoholics.
Drugs that have high affinity for and extensive binding to, serum albumin are
generally acidic drugs and include warfarin, NSAIDs (including COX-2
inhibitors), phenytoin, lorazepam, valproic acid and sulfamethoxazole. A good
clinical example of this is the COX-2 inhibitor celecoxib. Since celecoxib by itself
does not affect platelet function or bleeding time, it is an appropriate antiinflammatory/analgesic treatment option for patients taking warfarin. However,
shortly after its introduction, a number of studies found that celecoxib (protein
bound 97%) could significantly elevate the international normalized ratio, or INR,
in patients taking warfarin (99% bound) and that it was most likely due to a drug
displacement interaction.
Inducers of CYP450: rifampin, carbamazepine, smoking, phenytoin and the
barbiturates, all of which induce multiple isoforms of CYP450 resulting in
reduction of plasma concentration of the object drug that being metabolized by
CYP450 isoforms.
Inhibitors of CYP450: there are some drugs that can inhibit several different
isoforms of P450 (with differing potencies), such as ketoconazole, fluconazole,
amiodarone and ritonavir. Resulting in increasing plasma concentration of the
object drug that being metabolized by CYP450 isoforms. Common potent
inhibitors: ciprofloxacin, fluvoxamine, fluconazole, fluvoxamine, fluoxetine,
paroxetine, macrolides e.g. erythromycin, clarithromycin. Azole antifungals e.g.
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voriconazole, itraconazole, ketoconazole. Protease inhibitors e.g. indinavir and
ritonavir. Saquinavir grapefruit juice cimetidine diltiazem, verapamil. Clopidogrel
is converted to its active form by either CYP2C19 (major) or CYP3A4 (minor),
depending on the concentration of the drug that recognition a few years back that
certain PPIs, especially omeprazole, could inhibit CYP2C19-mcdiated clopidogrel
activation leading to therapeutic failure. Inhibitory of CYP2D6 -~ such fluoxetine,
paroxetine and others — can reduce the effectiveness of codeine or tamoxifen, the
latter having become a concern in the breast cancer arena.
Unlike induction, which may take days to appear and weeks be Fore it reaches its
maximal effect, the effects ofCYP450 inhibitors can be observed after
administration of the first dose of an inhibitor and be maximal when the inhibiting
drug reaches steady state levels.
Alteration of urinary excretion:
Alteration of urinary pH: Urinary pH influences the ionization of weak acids and
bases and thus affects their reabsorption and excretion. A nonionized drug more
readily diffuses from the glomerular filtrate into the blood. More of an acidic drug
is nonionized in an acid urine than in an alkaline urine, where it primarily exists as
an ionized salt. Thus, more of an acidic drug (e.g., a salicylate) diffuses back into
the blood from an acid urine, resulting in prolonged and perhaps intensified
activity. The risk of a significant interaction is greatest in patients who are taking
large doses of salicylates (e.g., for arthritis). Opposite effects are seen for a basic
drug like dextroamphetamine.
Alteration of active transport: Probenecid increases the serum levels and
prolongs the activity of penicillin derivatives, primarily by blocking their tubular
secretion. Such combinations have been used to therapeutic advantage
Inhibition of OATs (organic anionic transporters) or OCTs in renal proximal tubule
cells decreases the cellular uptake of their substrates from renal blood and their
subsequent clearance into urine. As a consequence, the clearance of drugs that are
eliminated to a significant degree by renal tubular secretion may be reduce
For example, the ability of probenecid to reduce the renal clearance of penicillin is
at least partially due to competition for OAT', m the renal tubule. While the
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pcnicillin/probenecid interaction had some therapeutic and cost advantages at one
time, other interactions at the OATs may improve more problematic. For example,
NSAIDs are known to inhibit the excretion of the methotrexate by inhibiting
OATs, and the combination, as might be inadvertently used by a rheumatoid
arthritis patient, could lead to significant toxicity.
Dr. Qutaiba Ahmed Ibrahim
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