Definition of terms
The concentration of a drug in the body can be increased or decreased by the simultaneous administration of one or more other active ingredients. Such a pharmacokinetic interaction can result in a reduced or increased effectiveness of the medicinal substance as well as undesirable effects or toxic effects. The term pharmacokinetics signals that the interaction takes place on different levels in the organism and that different mechanisms can be involved. This includes the absorption of the drug in the intestine, for example, its distribution, metabolism in the liver and other organs, and its excretion via the kidneys and biliary tract.
Interactions at the level of uptake of the drug (absorption)
Resorption describes the absorption of a drug from the application site such as the gastrointestinal tract into the bloodstream. It mostly takes place in the small intestine. If another active ingredient changes the length of time the drug stays in the gastrointestinal tract or the pH value, forms so-called complexes with the drug, or influences the intestinal flora, absorption can be impaired. A typical example is the inactivation of antibiotics from the groups of tetratzyclins or fluoroquinolones through complex formation with so-called polyvalent cations such as Ca2 +, Fe2 +, Zn2 +, Mg2 + or Al3 +.
Interactions at the level of distribution in the organism (distribution)
Distribution includes the distribution of the active ingredient throughout the bloodstream, tissues and various organs. The distribution volume is used as a measure of the distribution. The distribution depends, among other things, on the blood flow to the organs, the protein binding of the active substance in the blood and on the physicochemical properties of the medicinal substance. The protein binding acts as a kind of depot from which free, unbound active ingredient can be released. Only the unbound portion of the active ingredient is effective. If several drugs are administered at the same time, they can compete for the binding sites on the plasma proteins and displace themselves from the binding sites, which describes a further form of a pharmacokinetic interaction. Such interactions are seldom clinically relevant and only if the drug has a high protein binding, has a relatively small volume of distribution and has a narrow therapeutic range. An example of this would be an interaction between the anti-epileptic drug phenytoin and the analgesic drug diclofenac (administered systemically), which can increase the plasma concentration and toxicity of phenytoin.
Interactions at the level of metabolism (metabolism)
The metabolism describes the change in the biochemical structure of the active ingredient in the organism with the frequent goal of inactivating the active ingredient and making it water-soluble and thus facilitating its excretion via the kidneys or the intestine. In some cases, active substances are first formed through metabolism (in the case of so-called inactive prodrugs) or the already active substance is converted into intermediate products (metabolites) that are also active. An active ingredient can possibly be metabolized into dozens of metabolites. Enzymes from the cytochrome P-450 enzyme system (CYP enzymes) often play a role in the conversion. The most common one is CYP3A4, which is involved in the metabolism of more than 70% of all drugs. Pharmacokinetic interactions often take place at the level of these CYP enzymes. The enzymes can be inhibited (inhibition) or activated (induction) to a greater extent. An interaction can already take place in the intestinal cells or during the first passage through the liver, in the so-called first-pass metabolism. If a relevant proportion of the active ingredient is already broken down by enzyme induction, less active ingredient reaches the system cycle and so-called bioavailability decreases (high first-pass effect). For some of these CYP enzymes there are genetically determined differences in activity (polymorphisms). One example is CYP2D6, for which approx. 8% of Central Europeans have a reduced function and are so-called poor metabolizers (slow metabolizers). With the same dosage of the active ingredient, the active ingredient concentration can be increased in poor metabolizers and the risk of toxicity increases.
Interactions can also take place at the level of drug transporters. These play a role, for example, in the absorption of medicinal substances into the intestinal or liver cells or in their excretion in the biliary tract or renal tubules. The known representatives include the P-glycoprotein transporters as a product of the MDR1 gene or the OATPs (OATP1B1, OATP1B3, OATP2B1).
Interactions at the level of elimination
Elimination describes the final removal of pharmaceutical substances from the organism. The most important organs of elimination are the kidneys and the liver. Interactions can also occur at the level of elimination, which either accelerate or delay elimination. For example, antihypertensive drugs from the ACE inhibitor group promote the excretion of sodium in the kidneys. As a result, less sodium is available in the tubule and more lithium is therefore reabsorbed, which increases the lithium level. By influencing renal transporters, clinically relevant interactions may also occur. NSAIDs like ibuprofen can increase the toxicity of methotrexate by competing for organic anion transporters (OAT3).
In the previously available services for drug interactions, only the relationship between two active ingredients is shown for the assessment of pharmacokinetic interactions. It is, however, much more relevant, but also many times more complex, to depict the pharmacokinetic interaction of several active substances, i.e. the simultaneous influence of several other active substances on a medicinal substance. For example, a single inhibitor of a breakdown pathway will have a different effect on the concentration of a drug in the organism than the simultaneous administration of two or more inhibitors of this breakdown pathway or even the combination of an inhibitor and an inducer. The quantitative assessment of multiple interactions may require completely different measures in the clinical management of the drug combination.
We model these multiple effects and provide estimates for AUC changes, insofar as this appears reasonable from pharmacological considerations. We use the in vivo mechanistic static model (IMSM) by Tod et al. 2019. We only consider linear-kinetic interactions.