DRUG INTERACTIONS IN ANIMALS: WHAT HAPPENS WHEN WE MIX DRUGS? Mark G. Papich, Professor of Clinical Pharmacology, Diplomate ACVCP
North Carolina State University, Raleigh, North Carolina, USA
Veterinarians often administer combinations of drugs without considering possible interactions that may occur. Many interactions and incompatibilities are possible considering the vast number of drugs available that may be used in combination. Interactions can result in a lack of therapeutic effect or toxicity. A distinction should be made between drug interactions that occur in vitro (such as in a syringe or vial) from those that occur in vivo (in the patient). Veterinarians frequently mix drugs together in syringes, vials, or fluids before administration to animals. These in vitro reactions also have been called pharmaceutical interactions. A drug interaction of this nature may form a drug precipitate, a toxic product, or inactivate one of the drugs to unknowingly administer an ineffective compound. Compounding drugs that are incompatible may cause in vitro drug interactions. Drug interactions can also occur as the result of drugs interacting in the patient (in vivo). Many interactions are possible that affect the pharmacokinetics (absorption, distribution, or elimination) or the pharmacodynamics (mechanism of action) of the drug. Chemical Incompatibilities: These reactions occur as a result of interactions between active ingredients, inactive ingredients, vehicles, and preservatives. Veterinarians should not admix drug solutions without consulting a pharmaceutical reference (textbook of IV drug interactions or USP,for example) or the drug manufacturer. The drugs listed below have often been cited as being incompatible with other drugs or solutions. Examples of Interactions: Antibiotics: aminoglycosides (gentamicin, tobramycin), ampicillin, tetracyclines, chloramphenicol, penicillins, and amphotericin B. These drugs can be incompatible if mixed with other drugs or solutions. (eg, mixing gentamicin with most other drugs results in inactivation). Fluoroquinolones are mixed with a variety of solutions, flavorings, and other enhancers to make it easier to administer these drugs to horses, exotic animals, and cats.However, fluoroquinolones are notorious for their ability to chelate with some compounds, particularly metals. A recent in vitro study tested the compatibility of oral fluoroquinolone drugs with various mixtures that included: molasses, syrup, some pharmaceutical flavored syrups, tuna fish flavoring, corn syrup, and vitamin and mineral supplements. The ingredient that had the most effect was the vitamin and mineral supplement. The mineral and vitamin supplement (Lixotinic), which contained a significant concentration of iron and calcium, decreased fluoroquinolone concentrations by approximately 50%. Solutions may be incompatible with other solutions because of ionic interactions. For example sodium bicarbonate (NaHCO3) will react with calcium-containing solutions, forming calcium carbonate. IV fluoroquinolones should not be mixed with cationcontaining fluid solutions. Admixing tetracyclines with calcium-containing solutions will result in precipitation. Do not mix salts of hydrochloric acid (HCl) (eg, dobutamine HCl, dopamine HCl, and epinephrine HCl) with alkaline solutions. Vitamin B1 (thiamine hydrochloride) is unstable in alkaline solutions and should not be mixed with alkalinizing solutions, carbonates, or citrates.
Potential problems with drug stability: Because many drugs are not in a form that is ideal for the species being treated, (eg, cats, exotic animals, pet birds), the tablets have been crushed, capsules reformulated, and solutions altered to make a more convenient and palatable oral dose form. However, when protective coatings are disrupted, and the vehicles altered, the stability of the product may be compromised. In some instances, the only change is a slight alteration of pH. But, according to the USP-NF, improper pH ranks with exposure to elevated temperature as a factor most likely to cause a clinically significant loss of drug. A drug solution or suspension, may be stable for days, weeks, or even years in its original formulation, but when mixed with another liquid that changes the pH, it degrades in minutes or days. It is possible that a pH change of only one unit could decrease drug stability by a factor of ten or greater. Addition of a water-based solution to a product to make a liquid solution or suspension can hydrolyze some drugs (betalactams, esters). Some drugs undergo epimerization (steric rearrangement) when exposed to a pH range higher than what is optimum for the drug (for example this occurs with tetracycline at a pH higher than 3). Other drugs are oxidized, which is catalyzed by high pH, and renders the drug inactive. Oxidation is often visible through a color change. Loss of solubility may be observed through precipitation. Veterinarians and pharmacists are obligated to be cognizant of the potential for interactions and interferences with stability. Interactions That Affect Absorption: Interactions related to stomach acid: Some drugs need an acid environment to dissolve prior to GI absorption. Drugs such as antacid compounds or H2 blockers (cimetidine) will suppress stomach acidity which may decrease the absorption of certain drugs. For example decreasing the stomach acidity will decrease oral absorption of the antifungal drugs ketoconazole and itraconazole. They are better absorbed in an acid environment. By contrast, absorption of other drugs (penicillins or omeprazole for example) is favored when stomach acidity is low because they are less stable in an acid medium. Divalent cations (Mg++, Ca++) in antacid drugs will bind to tetracyclines and prevent absorption from the GI tract. Di- and tri-valent cations especially Fe+3, Mg+2, and Al+3, will bind and prevent absorption of fluoroquinolone antibiotics. Gastrointestinal protectants such as sucralfate (contains aluminum), anticids (containing Mg+2 and/or Al+3) will decrease absorption of fluoroquinolone antibiotics. Interactions Involving the MDR Efflux Pump (P-glycoprotein): The multi-drug resistance (MDR) efflux pump, also known as p-glycoprotein (P-gp) can be involved in several important drug interactions (Lin 2003). P-glycoprotein is responsible for pharmacokinetic changes because it is located in the intestine, biliary tract, liver, placenta, and blood-brain-barrier (Preiss, 1988). The best known pharmacokinetic reactions are those that pump drugs into the intestinal lumen, thereby decreasing systemic absorption and increasing drug clearance from the body. The Pgp in the brain capillaries that form the blood brain barrier keeps compounds from causing toxicity in the central nervous system (CNS). P-glycoprotein is an integral part of the BBB and participates in neuroprotection of the brain by regulating drug entry (Lechardeur et al 1996). Inhibitors of P-gp of veterinary importance include ketoconazole, cyclosporine, calcium- channel blockers (diltiazem), and antiarrhythmics (lidocaine and quinidine). Cyclosporine is both a substrate, and an inhibitor of P-gp.Rifampin and corticosteroids can act as inducers (increase the activity) of P-gp. Drugs that inhibit P-gp, such as ketoconazole or cyclosporine, may cause drug interactions. For example, quinidine is an inhibitor of P-glycoprotein and will
increase the serum concentrations of digoxin. Ketoconazole will inhibit P-gp in the intestine and increase oral absorption of other drugs, including cyclosporine. Concurrent administration of ketoconazole has been known to decrease dose requirements for cyclosporine by one-third. Cyclosporine may inhibit the P-gp in the blood-brain-barrier and increase the CNS concentration of some drugs, such as the ivermectin group.There are anecdotal reports of animals that have received cyclosporine and ivermectin like drugs concurrently and subsequently developed clinical signs consistent with ivermectin toxicosis. One must be aware that drugs that inhibit P-gp to alter cyclosporine pharmacokinetics, also may affect other drugs. For example, if one uses ketoconazole to increase oral absorption of cyclosporine in a patient, other drugs, such as digoxin, that are substrates also will have increased absorption and higher plasma and CNS concentrations. Interactions that Affect Hepatic Drug Clearance (ClH): Many drugs must be biotransformed by microsomal enzymes in the liver in order to make them more water soluble for excretion into the bile or urine. Drugs metabolized by the liver can undergo two phases of reactions, the Phase I reactions, and Phase II reactions. The Phase I reactions metabolize the drug to a more water-soluble compound. These reactions often are oxidative, but other reactions, such as reduction, also occur. The Phase II reactions are conjugation. The best known example is that of conjugation with glucuronic acid, but other conjugation reactions with amino acids, acetylate and sulfate are possible. Drugs that affect the liver's biotransformation enzymes can cause clinically significant drug interactions. The Cytochrome P450 enzymes participate in the metabolism of drugs. Induction, or inhibition of these enzymes have been studied in great detail in humans and families of these enzymes have been identified. CYP-3A4 are probably the most important of this group because they have the largest number of substrates (about half the drugs currently prescribed). However, CYP-2D6, -1A2, -2C9, and -2C19 also can be important. Animals also have these families of enzymes, although the activity of each group is not the same as in humans (Chauret et al,1997). Of the the species compared,(dog, cat, and horse) none of them resemble the same pattern as humans. Microsomal Enzyme Induction: Drugs and compounds can increase the activity of the cytochrome P-450 (CYP) enzymes. Some of these enzymes also may reside in the intestine. As a result of this increase in activity (induction), drugs metabolized by the same enzymes will be cleared faster. The enzymes most commonly affected by induction are the mixed-function oxidases, (Phase I oxidation reactions). During induction, there is an increase in activity of the enzymes as well as an increase in the content of the enzymes in the endoplasmic reticulum. Some drugs are specific in their inducing ability. For example, a drug may induce one group of enzymes, without affecting another group. The drugs most affected by enzyme inhibition are those that undergo metabolism by the hepatic enzymes and are lipid soluble. Affected drugs usually have a low hepatic extraction ratio. The time for induction to occur is usually 2 to 3 weeks of exposure and it may take 2 to 3 weeks for induction to return to normal after the inducing drug is withdrawn. Microsomal Enzyme Inhibition: Hepatic microsomal biotransformation enzymes also may be inhibited by certain drugs and compounds. The inhibition occurs via a competitive binding to form an inactive drug-enzyme complex. The time for inhibition to occur is almost immediate. In many cases it is actually a
metabolite of the drug that is responsible for enzyme inhibition. However, noncompetitive inhibition also is possible when the drug is not a substrate for the enzyme. Examples of hepatic microsomal enzyme inhibition, include: cimetidine inhibition of metabolism of theophylline, chloramphenicol inhibition of metabolism of barbiturates, ketoconazole inhibition (by as much as 85%) metabolism of cyclosporine, ketoconazole inhibition of metabolism of prednisolone, and ethanol or 4-methyl pyrazole inhibition of alcohol dehydrogenase involved in converting ethylene glycol to toxic metabolites (this effect is utilized to treat toxicosis). One example of enzyme inhibition that has clinical consequences in people (listed here for interest only) is the inhibition of metabolism of acetaminophen (Tylenol) by consumption of alcohol: This inhibition leads to accumulation of metabolites that are hepatotoxic. Interactions that Involve Drug Protein Binding: Certain drugs, are known to displace drugs from protein binding sites and increase the fraction of drug unbound. For most drugs, the amount of protein in the plasma (and subsequently the number of available drug binding sites) greatly exceeds the concentration of drug in the plasma and binding is rarely saturated. Interactions that involve displacement of protein-bound drugs are therefore rare unless there is severe hypoproteinemia or the drug is so highly protein bound that it occupies most of the binding sites. Only drugs that are highly protein bound (approximately greater than 85%), exhibit high clearance, and have a low therapeutic index are likely to be involved in protein binding interactions of clinical significance. REFERENCES: Chauret N, Gauthier A, Martin J, and Nicoll-Griffith DA. In vitro comparison of cytochrome P450-mediated metaolic activities in huma, dog, cat, and horse. Drug Metabolism & Disposition 25: 1130-1136, 1997. Lechardeur D, Phung-Ga V, Wils P and Scherman D. (1996) Detection of multidrug resistance of p-glycoprotein in healthy tissues: the example of the blood brain barrier. Ann Biol Clin 54: 31-36. Lin JH. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Advanced Drug Delivery Reviews 55: 53-81, 2003. Preiss R. (1998) P-glycoprotein and related transporters. Int J Clin Pharm Ther 36: 3-8. United States Pharmacopeia. USP-DI Drug Information for the Health Care Professional, 2007. Rockville, MD. Proceedings of the WSAVA Congress, Sydney, Australia 2007
Phase II Protokoll AGO-GYN 8 Wirksamkeit, Verträglichkeit und Sicherheit von Temsirolimus beim platinrefraktären Ovarialkarzi- nom und beim fortgeschrittenen oder rezidivierten Endometriumkarzinom Eine Studie der Arbeitsgemeinschaft Gynäkologische Onkologie: AGO Studiengruppe Studienleiter nach AMG Sponsor AGO Research GmbH EudraCT Nr. 2011-000299-33 Ve