Prodrugs parenteral administration

SA Varia, VJ Stella. Phenytoin prodrugs VI In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats. J Pharm Sci 73(8) 1087-1090, 1984. 

H. Bundgaard, C. Larsen, E. Arnold, Prodrugs as Drug Delivery Systems XXVII. Chemical Stability and Bioavailability of a Water-Soluble Prodrug of Metronidazole for Parenteral Administration , Int. J. Pharm. 1984, 18, 79-87. 

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. 

S. A. Varia, V. J. Stella, Phenytoin Prodrugs VI In vivo Evaluation of a Phosphate Ester Prodrug of Phenytoin after Parenteral Administration to Rats , J. Pharm. Sci. 1984, 73, 1087-1090. 

Bundgaard, H., C. Larsen, and E. Arnold. 1984a. Prodrugs as drug delivery systems. XXVII. Chemical stability and bioavailability of a water-soluble prodrug of metronidazole for parenteral administrated. 

Explain the meaning of the terms (a) lead compound, (b) excipient, (c) parenteral administration, (d) pharmacophore and (e) prodrug. 

Although it is not common to prepare prodrugs for parenteral administration, some situations may occur in which this might be useful in increasing the amount of active moiety that will reach the systemic circulation. 

C se B. When a prodrug is pharmacologically inactive, subject to important presystemic and/or systemic biotransformation to the active moiety, and intended for both oral and intravenous administration, two practical situations may occur the active moiety is available for parenteral administration or the active moiety cannot be administered intravenously to humans for practical, safety, or ethical reasons. 

A synthesis of (137), a highly hydrosoluble phosphonoojymethyl prodrug of benzimidazole (136) has been described by Castillo et al. The compound (137) improved the aqueous solubility of its precursor (136) 50 000 times and was stable at neutral pH. Evaluations of the prodrug (137) in vitro and in vivo showed a fasciolicidal activity. The in vivo results proved that (137) offered a considerable reduction in the dose administered compared to the compound (136) (4mgkg in comparison to 15 mgkg ) while achieving similar effects via parenteral 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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