Toxicology of Drug-Drug Interactions


Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic.
Drug-drug interactions (DDIs) are one of the commonest causes of ADRs and these manifestations are commons in the elderly due to poly-therapy.

Classification of Drug-Drug Interactions

Drug-Drug Interactions can be classify into two main groups:

1. Pharmacokinetics:

 Involves absorption, distribution, metabolism and excretion, all of them being associated with both treatment failure or oxicity;

2. Pharmacodynamics

Pharmacodynamics may be divided into three subgroups: 

  • i). direct effect at receptor function
  • ii). interference with a biological or physiological control process and
  • iii). additive/opposed pharmacological effect.

Pharmacokinetic interactions are often considered on the basis of knowledge of each drug and are identified by controlling the patient’s clinical manifestations as well as the changes in serum drug concentrations.  They involved all the processes from absorption up to excretion that will be now described.

a. Absorption

The change in gastric pH.

The complexity of the gastro-intestinal tract, and the effects of several drugs with functional activity on the digestive system, represent favourable conditions for the emergence of DDI that may alter the drug bioavailability.
Several factors may influence the absorption of a drug through the gastrointestinal mucosa. The first factor is the change in gastric pH. The majority of drugs orally administered requires, to be dissolved and absorbed, a a gastric pH between 2.5 and 3. Therefore, drugs able to increase gastric pH (i.e., antacids, anticholinergics, proton pump inhibitors [PPI] or H2-antagonists) can change the kinetics of other co-administered drugs.
In fact, H2 antagonists (e.g., ranitidine), antacids (e.g., aluminium hydroxide and sodium bicarbonate) and PPI (e.g., omeprazole, esomeprazole, pantoprazole) that increase the gastric pH lead to a decrease in cefpodoxime bioavailability, but on the other hand, facilitate the absorption of beta-blockers and tolbutamide.
Moreover, antifungal agents (e.g., ketoconazole or itraconazole), requires an acidic environment for being properly dissolved, therefore, their co-administration with drugs able to increase gastric pH, may cause a decrease in both dissolution and absorption of antifungal drugs. Therefore, antacid or anticholinergics, or PPI might be administered at least 2 h after the administration of antifungal agents.
Similarly, the administration of drugs able to increase the gastric pH (see above) with ampicillin, atazanavir, clopidogrel, diazepam, methotrexate, vitamin B12, paroxetine and raltegravir are not recommended.
In contrast, the ingestion of drugs that cause a decrease in gastric pH (e.g., pentagastrin), may have an opposite effect. It is worth noting that severity of DDIs caused by alteration of gastric pH mainly depends on pharmacodynamics characteristics of the involved drug, in terms of narrow therapeutic range.

The formation of complexes.

Another factor that modifies the drug absorption is the formation of complexes. In this case, tetracyclines (e.g., doxycycline or minocycline) in the digestive tract can combine with metal ions (e.g., calcium, magnesium, aluminum, iron) to form complexes poorly absorbed. Consequently certain drugs (e.g., antacids, preparations containing magnesium salts, aluminum and calcium preparations containing iron) can significantly reduce the tetracyclines absorption. Analogously, antacids reduce the absorption of fluoroquinolones (e.g., ciprofloxacin), penicillamines and tetracyclines, because the metal ions form complexes with the drug. In agreement, was observed that antacids and fluoroquinolones should be administered at least 2 h apart or more.
 Cholestyramine and colestipol bind bile acids and prevent their absorption in the digestive tract, but they can also bind other drugs, especially acidic drugs (e.g., warfarin, acetyl salicylic acid, sulfonamides, phenytoin, and furosemide). Therefore, the interval between the administration of cholestyramine or colestipol and other drugs may be as long as possible (preferably 4 h).

Motility disorders

Motility disorders represent the third factor involved in absorption DDIs. Drugs able to increase the gastric transit (e.g., metoclopramide, cisapride or cathartic) can reduce the time of contact between drug and mucosal area of absorption inducing a decrease of drug absorption (e.g., controlled-release preparations or entero-protected drugs).
For example, metoclopramide, may accelerate gastric emptying, hence decreasing the absorption of digoxin and theophylline whereas it can accelerate the absorption of alcohol, acetylsalicylic acid, acetaminophen, tetracycline and levo-dopa.
Finally, iron can inhibit the absorption of levodopa and metildopa.

Modulation of P-glycoprotein (P-gp) intestinal

P-gp or gp-120 for its molecular weight, is a transmembrane protein encoded by the human multidrug resistance gene-1 belonging to the adenosine triphosphate-binding cassette (ABC) superfamily, together with other 41 members grouped in 7 families (A to G).
 Localized in liver, pancreas, kidney, small and large intestine, adrenal cortex, testes and leukocytes, P-gp plays a protective role influencing the trans membrane drugs diffusion thus reducing their absorption or increasing their excretion or limiting their tissues distribution (i.e., central nervous system, foetal and gonadic tissues).
P-gp regulates the intestinal absorption of drugs (it is present on the luminal surface of enterocytes) and promotes their excretion (it is present on the side tubular of epithelium renal and biliary side of hepatocytes). Therefore, the administration of drugs able to stimulate to inhibit the activity of P-gp, can induce the development of DDI. The P-gp inhibition can significantly increase the bioavailability of drugs poorly absorbed.
The DDIs on P-gp might induce a clinical effect in presence of drugs with a low therapeutic index (e.g., digoxin, theophylline, anticancer drugs) when co-administered with macrolides (e.g., erythromycin, roxithromycin, clarithromycin), PPIs (e.g., omeprazole or esomeprazole) or anti-arrhythmic drugs (e.g., dronaderon, amiodarone, verapamil or diltiazem).
Many drugs (but not all) that are transported by P-gp are also metabolized by cytochrome P450 (CYP) isoform 3A4 (e.g., cyclosporine, antiepileptic drugs, antidepressant, fluoroquinolones, quinidine and ranitidine), which can confound interpretation of interactions 

b. Distribution

Usually, drugs are transported through a binding to plasma and tissues proteins. Of the many plasma proteins interacting with drugs, the most important are albumin, α1-acid glycoprotein, and lipoproteins. Acidic drugs are usually bound more extensively to albumin, while basic drugs are usually bound more extensively to α1-acid glycoprotein, lipoproteins, or both. Only unbound drug is available for passive diffusion to extravascular or tissue sites and typically determines drug concentration at the active site and thus its efficacy. Albumin represents the most prominent protein in plasma, it is synthesized in the liver and distributed in both plasma and extracellular fluids of skin, muscles and various tissues. Intestinal fluid albumin concentration is about 60% of that in the plasma. Since albumin has five binding sites (i.e., for warfarin, benzodiazepines, digoxin, bilirubin and tomoxifen), the main characterized are the site I and II.
Site I, also known as the warfarin binding site, is formed by a pocket in subdomain IIA, while site II located in subdomain IIIA is known as the Site I, also known as the warfarin binding site, is formed by a pocket in subdomain IIA, while site II located in subdomain IIIA is known as the benzodiazepine-binding site. Ibuprofen and diazepam are selective drug probes for site II.
Drugs that have a high degree of plasma protein binding are potentially more likely to be displaced by drug with greater affinity for the same binding site. 

c. Metabolism

The CYP enzyme family plays a dominant role in the biotransformation of a wide number of drugs. In man, there are about 30 CYP isoforms, which are responsible for drug metabolism and these belong to families 1-4, but only 6 out of 30 isoforms belonging to families CYP1, 2 and 3 (i.e., CYP1A2, 3A4, 2C9, 2C19, 2D6 and 2E1) are mainly involved in the hepatic drug metabolism.
The broad range of drugs that undergo CYP mediated oxidative biotransformation is responsible for the large number of clinically significant drug interactions during multiple drug therapy. Many DDIs are related to the inhibition or induction of CYP enzymes.


Inhibition-based DDIs constitute the major proportion of clinically relevant DDIs. In this process enzyme activity is reduced due to direct interaction with a drug, usually begins with the first dose of the inhibitor, while the extinction of inhibition is related to the drug half-lives.
The metabolic inhibition may be reversible (competitive, metabolic-intermediate complex, non-competitive) or irreversible, and clinical effects are influenced by basic mechanisms.

Reversible inhibition 

The competitive inhibition occurs when inhibitor and substrate compete for the same binding site on the enzyme. In this type of interaction, the inhibition mechanism is direct and is rapidly reversible.
The drugs are converted through multiple CYP dependent steps to nitroso-derivatives that bind with high affinity to the reduced form of CYP enzymes. Thus CYP enzymes are unavailable for further oxidation and synthesis of new enzymes is therefore, the only means by, which activity can be restored and this may take several days
It depends on the substrate-versus-inhibitor binding constant ratio, and on the relative concentrations of each species. Some of the inhibitors of CYP3A4 that act by this mechanism of inhibition include azole antifungal agents, some HIV protease inhibitors such as nelfinavir mesylate, and antihypertensives such as diltiazem.
Omeprazole, a CYP2C19 inhibitor, decreases the antiplatelet activity of clopidogrel by inhibiting the biotransformation of the clopidogrel pro drug into its active metabolite. Moreover, omeprazole treatment should be well evaluated in elderly patients due the possibility to induce the development of ADR.
Similarly, HIV protease inhibitors (i.e., saquinavir and ritonavir) increase sildenafil serum concentrations up to 11-fold.

Metabolic-intermediate complexes

The production of metabolic-intermediate complexes is an unusual form of inibition where the inhibitor binds only to the enzyme-substrate complex. The formation of a metabolic-intermediate complexes results from inhibitors that have an N-alkyl substituent. After the binding of inhibitor, the latter is oxidized by 3A4 and the resultant oxidized species of the inhibitor remains complexed with the reduced heme group of CYP3A4 forming a complex slowly reversible. Erythromycin is a well-known CYP3A4 inhibitors that use this mechanism of inhibition, whereas clarythromycin display reduced inhibitory effects with a good clinical efficacy.


In the non-competitive mechanism, the inhibitor and substrate do not compete for the same active site, because the presence of an allosteric site. Once a ligand binds the allosteric site the conformation of the active site changes, its ability to bind the substrate decreases and the product formation tails off. Many drugs are non-competitive inhibitors of CYP isoforms, as well as omeprazole and lansoprazole, and cimetidine. The duration of this type of inhibition may be longer if new enzymes have to be synthesized after the inhibitor drug is discontinued.

Irreversible inhibition

The metabolite resulting from the oxidation of the substrate by CYP3A4 becomes irreversible and covalently bound to 3A4, thus leading to a permanent inhibition of the enzyme. In the case of irreversible inhibition the critical factor is represented by the total amount rather than the concentration of the inhibitor to which CYP isoenzyme is exposed. Lipophilic and large molecular size drugs are more likely to cause inhibition. Two characteristics make a drug susceptible to inhibitory interactions: one metabolite must account for >30-40% metabolism of a drug and that metabolic pathway is catalyzed by a single isoenzyme.
Inhibitor will decrease the metabolism of substrate and generally lead to increased drug effect or toxicity of the substrate. If the drug is a pro drug the effect is decreased.

Metabolic induction

Drug interactions involving enzyme induction are not as common as inhibition-based drug interactions but equally profound and clinically important. Exposure to environmental pollutants as well as the large number of lipophilic drugs can result in induction of CYP enzymes. The most common mechanism is transcriptional activation leading to increased synthesis of more CYP enzyme proteins. The effect of induction is simply to increase the amount of P450 present and speed up the oxidation and clearance of a drug. The most commons enzyme inducers are rifampicin, phenobarbital, phenytoin,carbamazepine, and anti-tubercular drugs.

DDIs during excretion

The organs and vehicles of the drugs excretion (elimination) are kidneys, liver, lungs, feces, sweat, saliva, milk. The excretion through saliva, sweat and lungs (for volatile drugs) and milk has little quantitative significance, but the milk is important when the drugs can reach the baby during lactation.
Drugs are excreted mainly through:

  • Renal tubular excretion (glomerular filtration, tubular reabsorption and active tubular secretion)
  • Biliary excretion.

The drugs elimination from the body can undergo many interactions being excreted by another drug in this organ from, which it is excreted.
The kidney is the organ responsible for the elimination of drugs and their metabolites. The interaction may occur for a mechanism of competition at the level of active tubular secretion, where two or more drugs use the same transport system. An example is given by NSAIDs that determine the appearance of toxic effects caused by methotrexate when the renal excretion of the anti-proliferative drug is blocked.
It was also demonstrated that amoxicillin decreased the renal clearance of methotrexate.
However, this competition between drugs can be exploited for therapeutic purposes. For example, probenecid can increase the serum concentration of penicillins and cephalosporins, delaying their renal excretion and thus saving in terms of dosage. 
Management of patients treated with DDI 

  1. Early diagnosis
  2. Symptomatic and local  management
  3. Specific and systematic management and antidotes.

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