Prodrugs distribution

Figure 2 The permeability in Caco-2 cell monolayers as a function of distribution coefficient (octonol/water, pH 7.4) for 5-fluorouraciI and prodrugs. A sigmoidal relationship can be observed. (Replot from Ref. 26, with kind permission from Elsevier Science-NL, Amsterdam, The Netherlands.)...

The pyridinium portion of the previously mentioned partially saturated quinolizinium derivative 74 was reduced by sodium borohydride to yield compound 75, which was employed as a precursor to a radiolabeled methyl ether as a probe for the in vivo distribution of quinolizinium prodrugs (Equation 2) <2001BML519>. 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

In recent years, significant progress has been made in developing prodrug approaches to improve the water solubility, membrane permeability, in vivo distribution, and stability of peptides [193-197]. 

Cefuroxime is a second-generation cephalosporin. Orally, cefuroxime is available as the prodrug, cefuroxime axetil. Cefuroxime is very well absorbed from the gastrointestinal tract and widely distributed in the body. 

Absorption/Distribution - Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed. After administration of a single dose of fosamprenavir to HIV-1-infected patients, the... 

In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route. In many cases, the active drug molecule is sufficiently lipid-soluble and stable to be given as such. In some cases, however, an inactive precursor chemical that is readily absorbed and distributed must be administered and then converted to the active drug by biologic processes—inside the body. Such a precursor chemical is called a prodrug. 

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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