Prodrugs difficulties

B. Existence of mixed-type prodrugs Difficulties and Limitations Conclusion... 

What remains to be discussed, however briefly, are specific difficulties encountered in the design and development of prodrugs, as related to the viewpoints discussed above (Table 1.2). These difficulties may range from fair to prohibitive and can occur at all stages of the research and development... 

Table 1.3. Specific Difficulties in Prodrug Design and Development (modified from [22])a)...

The above problems appear to be the major sources of difficulty in prodrug research and development, not to mention possible complications during registration. No wonder, therefore, that so many medicinal chemists are critical of prodrugs. However, a lucid view cannot ignore the sunny side, in this case the mere existence of a number of successful prodrugs. Nabume-tone, oseltamivir, and pivampicillin are just a few examples that come to mind. 

Table 3 Specific difficulties in prodrug design and development... 

The difficulty in obtaining fibrinogen antagonists with high oral bioavailability has led to an interest in alternative routes of administration. For example, enhanced bioavailability of the ester prodrug DMP 755 compared... 

These substances metabolized within the CNS illustrate well one of the difficulties that may be encountered with prodrug kinetics. The prodrug may follow an ADME pattern perfectly well described by its systemic availability, volume of distribution, and both hepatic and renal clearances, but still have a pharmacological effect whose dependency on blood kinetics is only indirect. This is particularly true if the drug must diffuse through the blood-brain barrier, and is then metabolized by enzyme systems different from those found in the liver. 

The design of prodrugs in a rational manner requires, as stated by Bundgaard (9), that the underlying causes that necessitate or stimulate the use of the prodrug approach be defined and clearly understood. It may then be possible to identify the means by which the difficulties can be overcome. The rational design of the prodrug can thus be divided into three basic steps ... 

Several s mtheses of nucleotidephospholipids have been reported recently. For example, phospholipid-araC conjugates have been prepared and tested as prodrugs of arotC as inhibitors of the growth of a murine myeloma cell line. The most effective inhibitor was [13, = 1, R = Me(CH2)i4] solubility difficulties may have affected the testing of other analogues. 

---