The Use of Pro-Drugs in Improving Bioavailability and Pharmacokinetic Profiles - Essay Example

Pharmacology The use of pro-drugs in improving bioavailability and pharmacokinetic profiles. Introduction: Drugs are an important component in the treatment of diseases and conditions and this has led to the search for more effective drugs and the means to enhance the efficacy of the drug, while reducing the impact of side effects. A drug that is developed may have the essential structural configuration and physicochemical properties for providing a desired therapeutic effect, but it is not necessary that it possess the optimal molecular framework and properties to ensure delivery at the targeted site of action. In such cases only a small fraction of the drug reaches the targeted site, while the remaining fraction of the drug interacts with other sites, with consequences of inefficient drug delivery and undesirable side effects. Insufficient aqueous solubility and protein binding characteristics of that inhibit crossing blood brain barriers are two examples of the manner in which the relevance of some drugs in clinical therapeutics gets limited. It is against this background that pro-drugs and their utility in overcoming the limitations of bioavailability and pharmacokinetics profiles has become a significant subject of study in pharmacology (Shek, 1994). What are Pro-Drugs? A look at the history of pro-drugs shows that understanding of pro-drugs and their pharmaco-kinetics in the human body came more as a result of after the introduction of the drugs for therapeutic purposes. The introduction of phenacetin as a therapeutic agent dates back to 1887, but it took till 1949 for the realization that paracetamol was the active metabolite of phenacetin, which resulted in the gradual erosion of phenacetin as a therapeutic agent to be replaced by paracetamol, demonstrating that many of the pro-drugs result from metabolism in the human body. (Pleuvry, 2006). This understanding of the possibility of enzymatic action to create active therapeutic agents has now become the basis of overcoming the problems of potential drug candidates demonstrating poor therapeutic effects, because of poor bioavailability and pharmacokinetic profiles. Kratz et al, 2008, define pro-drugs as “derivatives of a drug that are metabolized or activated in the body to release or generate the active drug – if possible at the site of action”. Thus pro-drugs are chemically modified versions of the pharmaceutical agent that needs to undergo a transformation in vivo for the release of the active drug. This feature of pro-drugs is employed to enhance the bioavailability and pharmacokinetic properties of pharmacologically potent compounds. In a majority of the cases pro-drugs are simple chemical derivatives that are transformed by one or two chemical or enzymatic processes to provide the active parent drug. In other cases pro-drugs may be made up of two pharmacologically active agents that are fused into a single molecule for the purpose of each of the constituents acting as a pharmaceutically enhancing agent for the other, in what we may take as co-drugs (Rautio, et al, 2008). The current therapeutic use of pro-drugs is to the extent of five to seven percent of all pharmaceutical agents approved worldwide. The realization of the potential benefits that pro-drugs offer has seen an increase in the number of pro-drugs being approved for therapeutic use. In 2001 and 2002 fifteen percent of all pharmacological agents approved for therapeutic use were pro-drugs (Rautio, et al, 2008). Use of Pro-Drugs: The benefits of pro-drugs to the therapeutic use of pharmaceutical agents are many. Pro-drugs provides the means of to surmount the problems that seen in drug formulation and delivery, which include, poor stability in water, chemical instability, insufficient absorption in the digestive tract, rapid pre-systemic metabolism, insufficient penetration across the blood brain barriers into the brain, toxicity and local irritation. In addition pro-drugs offer the means to improve drug targeting and the development of a pro-drug of a drug that is already in existence may offer opportunities in life-cycle management. Thus the strategies involved in the development of pro-drugs are to improve oral absorption and aqueous solubility, enhance lipophilicity and transportation, and achieve delivery of the therapeutically active pharmacological agent at the required site (Rautio, et al, 2008). The oral bioavailability of a drug is impacted on by factors that include the aqueous solubility of the drug, propensity to be an efflux substrate, and quick and extensive hepatic metabolism and biliary excretion. An understanding of the factor that is negatively affecting the bioavailability and pharmacokinetic properties of the drug allows for the development of a pro-drug strategy to address this difficulty. In the case of most drugs the bioavailability is controlled by the fraction absorbed and clearance of the drug. Most of the pro-drugs developed are derived from parent drugs that have a low absorption, or minimal first pass metabolism. The problem of low absorption can be addressed through the development of a pro-drug that has an enhanced dissolution rate and aqueous solubility or permeability. Examples of such strategies can be seen in the pro-drug Pivampicillin. Pivampicillin is the pivaloylmethyl ester of ampicillin. It is bioconverted into ampicillin by esterases. The oral availability of ampicillin is limited to 32-55%, but by employing the pro-drug pivampicillin the bioavailability of ampicillin is increased to 87-94%. Another example lies in the antiviral adefovir dipivoxil and its pro-drug bis-(pivaloxymethyl)) ester of adefovir. The pro-drug is bioconverted by esterases and phosphodiesterases. The oral bioavailability of adefovir is less than ten percent, which is enhanced through the use of the pro-drug to 30-45% (Rautio, et al, 2008). Another area of important use of pro-drugs is to improve the lipophilicity. The use of a pro-drug strategy allows for the masking of polar and ionisable groups that are present within a drug molecule, which enables enhancing the oral availability of the parent drug. An example of this is in the pro-drug ximelagatran, which is an ethyl ester of melagatran, a direct thrombin inhibitor. The oral bioavailability of melagatram is only 3-7%, which is enhanced to 20% through the use of the pro-drug ximelagatran (Rautio, et al, 2008). Developments in molecular biology have enabled the identification and cloning of nutrient transporters along with an understanding of functional and structural characteristics and regulation of these proteins. This has enabled a pro-drug strategy that is targeted towards specific membrane transporters. The pro-drugs are so structured that they can be taken up by one of the endogenous transporters present in the intestinal epithelium. Such a strategy proves useful in the case of polar or charged drugs that demonstrate poor or negligible passive absorption. The peptide transporters make for attractive targets in this pro-drug strategy, as they found widely distributed in the small intestine and demonstrate adequate transport capabilities and wide substrate specificity. Examples of the use of carrier-mediated transport pro-drugs include valacyclovir and valganciclovir, which are L-valyl esters of acyclovir and ganciclovir, both of which demonstrate limited and variable bioavailability as a result of their high polarity (Rautio, et al, 2008). Aqueous solubility of the drug is an issue for bioavailability with parentally administered drugs. A commonly seen approach in pro-drug strategy to address this issue is through the increase in water solubility by the introduction of a polar promoiety to the parent drug. Fosphenytoin is an example of a pro-drug of this class. Phenytoin is a drug that is used for the treatment of acute seizures by the intravenous or intramuscular route. It suffers from the drawback of poor water solubility; Fosphenytion is a phosphate ester of phenytoin, which acting as a pro-drug removes this drawback (Rautio, et al, 2008). Drug delivery in oncology is of specials interest in pharmacology as a result of the narrow therapeutic window available. In addition is the requirement to target the tumour cells without affecting the normal healthy cells. The pro-drug strategy for specific target selection employs two different means called active targeting and passive targeting. In active targeting the strategy employed is based on the interaction between the carrier-linked pro-drug and the tumour-associated cell surface, like a receptor or an antigen. An example of the active targeting strategy is the antibody-directed enzyme pro-drug therapy (ADEPT). Initially a tumour associated mAb that is linked to a drug-activating enzyme is administered using the intravenous means of administration. This conjugate attaches itself to a specific antigen that expressed on the surface of the tumour cell. A low-molecular weight pro-drug is then administered after a suitable interval, which gets converted by the enzyme into a cytotoxic drug. Aminopeptidase is an example of drug-activating enzyme that is used with the pro-drug methotrexate in active targeting. In passive targeting it is the biochemical and physiological differences in the characteristics of a healthy and malignant tissue that is used as the means of developing pro-drugs (Kratz et al, 2008). Mutual pro-drugs are another way in which pro-drugs are employed to increase the efficiency of available drugs for the treatment of several diseases and conditions. Glucosamine is employed both as a drug and a nutritional supplement in conditions like joint ache and stiffness of the joints. Non-steroidal anti-inflammatory drugs (NSAID) like ibuprofen and diclofenac are used in the treatment of arthritis. Pro-drug containing elements of glucosamine and one of the NSAIDs offer twin advantages. In the first place there is reduced gastro-intestinal irritation as a result of the NSAID’s and a significant feature is that anti-arthritic activity demonstrated by such pro-drugs is more than the parent drugs used in combination, with some of this activity absent in the combined use of the parent drugs (Bhosle, et al, 2006) 2. Toxins and Poisons: Introduction: Doctor, 2002, defines a poison as “a material or chemical that is capable of producing a deleterious response in a biological system, seriously injuring function or producing death”. All substances have the capability of being a poison to the human body and it is the dose employed that decides this. Water is essential to the human body, but water consumed in very large excess can be poisonous to the human body by causing deleterious effects. Toxins are further typified as poisons that are produced by living organisms including plants, animals and micro-organisms to which human beings are either unintentionally or intentionally exposed. Toxins thus find their origin from other life forms (Doctor, 2002). Advances in molecular biology have enabled a better understanding of poisons and toxins and the benefits that can be derived from them in treating diseases and conditions that have remained refractory to pharmacological and surgical treatments. Toxins are already in use in treating such refractory diseases holding out hope that toxins could offer a clinical therapeutic means for the treatment of some of these diseases. Toxins also offer a host of other benefits. It may become possible to use toxins in the treatment of the dreaded disease cancer and other diseases. Toxins also may offer us the means to new drug delivery systems and also ways to prevent food poisoning. Poisons and toxins have thus opened a new and large field of pharmacological interest that offers the possibility of developing pharmacological agents and new ways of drug delivery systems to combat vexing diseases that have remained a challenge for the human species for a long time (Johnson, 1999). Uses of Poisons and Toxins: Clostridia Neurotoxins: From a deadly food poison to a front-line medicine that enables treatment sounds like a fairy tale, but it is the true story of the neurotoxins produced by various species of Clostridia. The neurotoxins produced by Clostridia are the causative agents of botulism and tetanus. The ability of these neurotoxins, with particular emphasis on botulinum neurotoxin family to interfere with neurotransmission is being exploited pharmacologically for the creation of several medications and currently represents the best therapeutic option in the treatment in a number of diseases and conditions. Clostridia neurotoxins have been found to possess a multi-domain structure, which is shared between the different proteins in the family. It has also been found that each of these domains contributes a specific function to the holotoxin. The widespread employment of recombinant expression approaches combined with solution of multiple crystallographic structures of individual domains has made it possible for proper exploration of the structure-functional relationships of the toxin domains to provide a more clear understanding. The advances that have resulted from the understanding that has resulted from such explorations have made it possible to consider the potential use of the individual domains for several purposes, which include the development of new therapeutic agents of clinical importance (Chaddock & Marks, 2006). Type-A botulinum toxin has been in use since 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. The number of indications for the use of Type-A botulinum toxin has gradually risen to the level where it is currently used for several focal dystonias, spasticity tremors, cosmetic applications, migraine and tension headaches, which have not responded satisfactorily to other modes of pharmacological and surgical treatment. The feature of botulinum toxin that has led to its therapeutic utility is its ability to specifically and potently inhibit involuntary muscle activity over long periods of time. Since the clostridia family produce more protein toxins than any other bacterial genus there remains a wide reservoir of toxins that have the potential for therapeutic exploitation. This exploitation of the neurotoxin domains may make it possible for developing more effective vaccines, delivery of therapeutic agents to the motor neuron and regulation of intracellular processes in specific cells (Chaddock & Marks, 2006). Spider Peptide Toxins: Developments in the field of mass spectrometry and peptide biochemistry have resulted in the isolation and identification of several novel peptide toxins from animal venoms in modern time, which has also caused research in spider venom to open up resulting in the identification of pharmacologically active spider peptide toxins. Several of these spider peptide toxins isolated from spider venoms share structural features, amino acid composition and consensus sequences that permit them to interact with related classes of cellular receptors. Spider peptide toxins have been identified as potential useful therapeutic agents, because of their antimicrobial properties and also as useful agents for the study of pore formation in cell membranes. Spider peptide toxins demonstrating nanomolar affinities for their receptors can be seen as potential pharmaceutical tools to promote the understanding of the physiological role of ion channels and also as the means for the development of therapeutic agents and strategies to deal with ion channel related diseases (Corzo & Escoubas, 2003). Voltage-activated sodium channels in combination with the potassium channels form the physiological basis of signal transmission in the nervous system. Coordinated functioning of these two ion channels is essential to the efficient impulse generation and propagation in the central and the peripheral nervous system. Sodium channel organization in the neuron has an impact on nerve activity that could progress to sensory and motor dysfunction. In humans this may be expressed in the pathophysiological mechanism involved in several neurological diseases that includes multiple sclerosis, epilepsy, stroke, peripheral neuropathies and neuropathic pain. With the spider peptide toxins demonstrating potential means to address ion channel organization and diseases related to it, the spider peptide toxins provide scope for development of therapeutic agents in the treatment of these neurological diseases associated with the ion channels (Corzo & Escoubas, 2003). Plant and Bacterial Toxins: There are several protein toxins that come from plant or bacterial origins, which have cytolosolic targets. Knowledge that has been gained from the study of these toxins has provided essential information of the mechanisms that can be employed to gain access to the cytosol, as well as the detailed information of endocytosis and intracellular sorting. These toxins include the toxins that show two moieties, one is the B-moiety that binds to cell surface receptors and the other the A-moiety possessing enzymatic activity and which enters the cytosol, along with molecules that demonstrate only enzymatically active moiety and hence find it difficult for entry into the cell. These toxins include the bacterial toxins Shiga toxins and diphtheria toxin and the plant toxins ricin and ribosome-inactivating proteins without the binding moiety, like gelonin. Toxins that have the binding characteristic can be employed as vectors that allow for translocation of epitopes, intact proteins and even nucleotides into the cytosol. The toxins can be further divided into two main groups based on entry into the cytosol. Some of these toxins enter from endosomes as a response to low endosomal pH, while the others including Shiga toxin and ricin are transported as far as the Golgi apparatus before they are translocated to the cytosol. Plant proteins that include gelonin are without a binding moiety and are taken up only through the fluid phase endocytosis and such plant proteins normally demonstrate low toxicity. Nevertheless they can be employed for testing for disruption of endosomal membranes moving on to cytosolic access of internalized molecules. On reaching the cytosol these plant proteins demonstrate high toxicity similar to the toxins having a binding moiety and through this becomes a tool that permits investigation for the study of endosomal disruption and induced transport to the cytosol. Plant and bacterial protein toxins thus become useful tools for the study of transport and cytosolic translocation and also offer the benefit of being used as vectors for transport to the interior of the cell (Sandviq & van Deurs, 2005). An attractive prospect in the treatment of cancer is the combination of the high selectivity of a monoclonal antibody with the powerful force of a potent cytotoxin. The allurement for this combination lies in the benefit of specific cell destruction, which is limited only to the extent of expression of the target. The two essential components comprising the specific antibody and the potent cytotoxin are there but marrying them ideally to provide a new therapeutic approach to management of cancer has proven a difficult task. However, plant and bacterial toxins may provide the means to this potentially powerful means to combat cancer. Immunotoxins possess extremely potent microbial and plant products. Psuedomonas exotoxin A and Diptheria toxin catalyze ribosylation of the elongation factor 2, while ricin hydrolyses adenine residues in 28S rRNA. The interruption of the protein synthesis happens through the means of a catalytic process that calls for less than a thousand toxin molecules per cell. In spite of the complications of immunogenicity and vascular leak syndrome that are normally linked with immunotoxins, the potential role of microbial and plant toxins in the treatment of cancer is demonstrated by the stunning response rates that have been seen with an anti-CD22 immunotoxin in chemo-therapy resistant hairy cell leukaemia (Polakis, 2005). Literary References Bhosle, D., Bharambe, S., Gairola, N., & Dhaneshwar, S. S. (2006). Mutual prodrug concept: Fundamentals and applications. Indian Journal of Pharmaceutical Science, 68, 286-94 Chaddock, J. A. & Marks, P. M. H. (2006). Clostridial neurotoxins: structure-function led design of new therapeutics. Cellular and Molecular Life Sciences, 63, 540-551. Corzo, G. & Escoubas, P. (2003). Pharmacologically active spider peptide toxins. Cellular and Molecular Life Sciences, 60, 2409-2426. . Doctor, V.S. (2002). Neuropsychiatric Aspects of Poisons and Toxins. In Stuart C. Yudofsky and Robert E. Hales (Eds.), The American Psychiatric Publishing Textbook of NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES (pp. 877-898). Arlington, VA: American Psychiatric Publishing, Inc., Johnson, A. E. (1999). CLOSTRIDIAL TOXINS AS THERAPEUTIC AGENTS: Benefits of Natures Most Toxic Proteins. Annual Reviews of Microbiology, 53, 551-575. Kratz, F., Muller, A. I., Ryppa, C. & Warnecke, A. (2008). Prodrug Strategies in Anticancer Chemotherapy. ChemMedChem, 3, 20-53. Pleuvry, J. B. (2006). Pharmaceutical effects of drug degradation products. Anaesthesia and Intensive Care Medicine, 7(2), 63-65. Polakis, P. (2005). Arming antibodies for cancer therapies. Current Opinion in Pharmacology, 5, 382-387. Rautio, J., Kumpulainen, H., Heimbach, T., Oliyar, R., Oh, D., Jarvinen, T & Savolainen, J. (2008). Prodrugs: design and clinical applications. Nature Reviews: Drug Discovery, 7, 255- 269. Sandviq, K. & van Deurs, B. (2005). Delivery into cells: lessons learnt from plant and bacterial toxins. Gene Therapy, 12(11), 865-872. Shek, E. (1994). Chemical delivery systems and prodrugs of anticonvulsive drugs. Advanced Drug Delivery Reviews, 14(2), 227-241. Read More