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Xenobiotics That Release Active Drugs

Huba Kalász1,* and Kornélia Tekes2

1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; e-mail: drkalasz@gmail.com

2Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; email: drtekes@gmail.com

*Address of correspondence to this author at the Department of Pharmacology and Pharmacotherapy, 1089 Budapest, Nagyvárad tér 4, Hungary



Xenobiotics are foreign chemical compounds to a living organism. The overwhelming majority of drugs belong to xenobiotics. In a broad sense, natural environmental compounds, pesticides, herbicides and industrial pollutants are also xenobiotics.

The word “drug” is generally used for such compounds that are used in medicine for treatment, cure, prevention or diagnosis, as well as enhancing either physical or mental well-being [1]. However, the same word (drug) is used to specify illicit psychoactive compounds. Neither strongly addictive hard drugs (illicit drugs) nor the less addictive variations (soft drugs) are treated here. The definition of soft drugs and hard drugs here solely means their ability to be either subjected to metabolic changes or to be resistant to them. The concept of soft drug and hard drug was stated by Ariëns [2] and Ariëns and Simonis [3]. One of the outcomes of this concept is the existence/construction of prodrugs that are pharmacologically inert compounds to be changed metabolically into active drugs. Today’s scope has definitely become wider. All drugs with pharmacologically active metabolites come under the heading “prodrugs”. More emphasis has been given to drug-metabolizing enzyme systems, on pharmacokinetics (lipophilicity, biological half life, of t½) and pharmacological potency of active metabolite of the parent drug. Even relatively less active metabolites may have importance in their clinical effect if they stay longer in the circulation than the more active but faster eliminating parent drug [4].

Pharmacokinetic behavior of a given drug can be substantially modified by pharmaceutical drug formulation methods. Recently, sophisticated techniques have been developed. Drug formulation makes the production of “slow release” or “extended release” drugs possible where the active compound is liberated continuously from the specially constructed matrix to give the proper level at the site of action for an adequate period of time. There is a wide variety of drug formulation techniques including application of the drug molecule in liposomes and lipoplexes, polymer conjugates, microparticles, nanoparticles, nanofibers, nanutubes, microemulsions, micelles, nanogels, dendrimers, pH-responsive carrier systems, receptor-mediated delivery systems,


direct intratumoral delivery tools, convection-enhanced delivery, polymer implants and electrochemotherapy [5]. Methodology of producing such drug formulations is an extremely developing field of research.

One of the most widely used preparations among the examples mentioned here is the liposomal doxorubicin (called Doxil®). It is a pegylated doxorubicin liposome where a single lipid bilayer membrane separates the internal aqueous compartment (containing doxorubicin) from the liposome surface coated with polyethylene glycol [5]. The mean diameter of the liposome is about 85 nm. Doxil® has a surfactant-free formulation that prolongs the time of liposomal doxorubicin in circulation, lowers drug distribution to healthy tissues, and promotes tumor uptake.

Adequate derivatization allows to prepare different salts or esters suitable for drug formulation for oral and/or intravenous administration. The same method is useful for masking bad taste and widely applied for the production of orally administered drugs, especially in pediatric practice. Such intentions were realized in the introduction of chloramphenicol palmitate, N-acetyl sulfisoxazole, N-acetyl sulfamethoxpyridazine, erythromycin esteolate and clindamycin palmitate.

According to the classical concept, lipophilicity of a drug (characterized by logP) is one of the most important physicochemical value predicting permeation through biological membranes to reach site of action. This classical concept was followed when lipophilic antiviral and anticancer prodrugs were administered to increase their penetration to the site of action where local metabolizing enzyme/enzymes can convert them to a pharmacologically active form. There is a wide scope of metabolic procedures including phosphate conjugation, hydrolysis, dealkylation, hydroxylation and decarboxylation.

The prodrug concept has blossomed and yielded practical results in many cases, such as in the use of L-DOPA to increase neurotransmission in the central nervous system of patients with Parkinson’s disease. The other well known application is the use of angiotensine convertase enzyme inhibitors in the treatment of hypertension and chronic heart failure (benazepril, enalapril, fosinopril, moexipril, etc.).

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