Most drugs, after administration in a conventional immediate- or controlled-release dosage form, freely distribute throughout the body, typically leading to uptake by cells, tissues, or organs other than where their pharmacological receptors are located. Figure 1 illustrates the distribution, metabolism, and elimination pathways of drugs following administration by different routes. The lack of target specificity for the most part can be attributed to the many barriers that the body presents to a drug. For example, a drug taken orally (most drugs are administered by this route, if possible) must withstand large
fluctuations in pH as it travels along the gastrointestinal (GI) tract as well as resist the attack by the enzymes that digest food and metabolism by microflora that reside there. To be systemically active, the drug must then be absorbed from the GI tract into the blood before it passes its region of absorption in the tract. Once in the blood, it needs to survive inactivation by metabolism and extraction (first-pass effects). To produce its therapeutic effect(s), the drug must then be able to selectively access and interact with its pharmacological receptor(s). The concentration of drug at the active site must also be adequate. Administration of drugs by parenteral routes avoids GI-associated problems, but deactivation and metabolism of the drug and dose-related toxicity are frequently observed. Furthermore, of all the paths the drug may take following administration, which one will produce the drug at its desired destination in adequate concentrations cannot be predicted. In addition, there are many diseases, such as rheumatoid arthritis, diseases of the central nervous system, some cancers, and intractable bacterial, fungal, and parasitic infections that are poorly accessible. To treat these diseases, high doses and frequent administration of drugs are often required, which lead to toxic manifestations, inappropriate pharmacodisposition, untoward metabolism, and other deleterious effects.
Table 1 lists the reasons for targeting drugs to their sites of action (3). Thus, a target-oriented drug delivery system offers potential to supply a drug selectively to its site(s) of action(s) in a manner that provides maximum therapeutic activity by preventing degradation or inactivation during transit to the target sites, protecting the body from adverse reactions because of inappropriate disposition, and delivering drugs in adequate concentrations and in predetermined, controlled-release kinetics. For drugs that have a low therapeutic index, targeted drug delivery may provide an effective treatment at a relatively low drug concentration. Other requirements for target-oriented drug delivery include that (i) the delivery system should be nontoxic, nonimmunogenic, and physically and chemically stable in vivo and in vitro; (lï) the drug carrier must be biodegradable (degradation products must also be safe) or readily eliminated without problems; and (ii'i) the preparation of the delivery system must be reasonably simple, reproducible, and cost effective.
Table 1 Reasons for Site-Specific Delivery of Drugs
Drug instability as delivered from conventional formulation Solubility Biopharmaceutical Low absorption High membrane binding Biological instability Pharmacokinetic and pharmacodynamic Short half-life
Large volume of distribution Low specificity Clinical Low therapeutic index Anatomical or cellular barriers Commercial
Source: From Ref. 3.
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