Prodrug formulations

Based on Mrs RP s extensive co-morbidities, including cardiovascular disease, plus her advanced age, it would seem entirely reasonable to consider the use of single-agent 5-FU-based chemotherapy in this situation, either administered intravenously or as an oral prodrug formulation. 

The biopharmaceutical consequences for prodrug formulations should be carefully evaluated. 

Cytotoxin that induces apoptosis by disrupting intracellular free Cd levels incorporated into chemotherapeutic prodrug formulations. 

R. Oliyai, V. J. Stella, Prodrugs of Peptides and Proteins for Improved Formulation and Delivery , Annu. Rev. Pharmacol. Toxicol. 1993, 32, 521-544. 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

Stevens PJ, Sekido M, Lee RJ. A folate receptor-targeted lipid nanoparticle formulation for a lipophilic paclitaxel prodrug. Pharm Res 2004 21 2153. 

There may not be any intention to develop an intravenous formulation for therapeutic use but it will usually be necessary to produce one for the purposes of the study. For prodrugs (i.e. where the main pharmacological activity comes from a metabolite), the appropriate intravenous comparator is the active metabolite. There are, however, some drugs that cannot be administered by the intravenous route, either because it would not be safe or because it is not technically feasible... 

Oral formulations of artemisinin and its derivatives are absorbed rapidly but incompletely. Peak plasma concentrations are reached in 1-2 h. A relative bioavailability of 43% was found for oral artemether compared to intramuscular administration. The absolute bioavailability of artesunate, the only derivative for which an intravenous formulation exists, was about 15%. Artesunate is extensively hydrolyzed to dihydroartemisinin in the gastro-intestinal lumen before first-pass metabolism in the gut wall and liver takes place. Artesunate acts like a prodrug with fast transformation into... 

The prodrugs are unstable in the presence of acid and therefore must be administered as an enteric-coated preparation or as a buffered suspension. Pantoprazole is also available in an intravenous formulation. The most commonly reported side effects are diarrhea and headache. Hypergastrinemia has been noted as a reaction to the marked reduction in acid secretion. Gastric carcinoid tumors have developed in rats but not in mice or in human volunteers, even after long-term use. 

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration. 

The usual dosage of chloramphenicol is 50-100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1-g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily. 

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