Drug Compounds that Exist Endogenously

While a substitute matrix can be used to prepare standard cahbrators for a drug compound that exists endogenously, VS/QCs should be prepared in the authentic matrix, regardless. VS data are used during method validation to characterize the intra- and inter-mn accuracy/precision and stability. QC data are used for assay performance monitoring and to accept or reject a run during in-study validation. 

Drug metabolism may be influenced by stereochemical factors if the molecule in question possesses one or more chiral centres. Examples of drugs that show stereochemical differences in rates of metabolism include a-methyldopa (where the (S) isomer is decarboxylated more rapidly than the (R) isomer) and the enantiomers of warfarin, which are reduced at different rates. The well-known endogenous compound mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) is chiral and exists as two enantiomers. When a racemic mixture of mevalonic acid is fed to animals, one optical isomer is absorbed and metabolised, while virtually all of the other isomer is excreted by the kidneys into the urine. 

The posterior route involves transport across the lipophilic retina and the RPE. Posterior elimination appears to occur via passive diffusion for lipophilic compounds although active transport mechanisms also exist for some endogenous compounds and also for some drugs. Forbes and Becker studied the vitreous elimination of radio-labeled iodopyracet in rabbits and found that while 300 pg labeled with 1 pCi was cleared rapidly with a half-life of three hours, 1.4 mg (also labeled with 1 pCi) was eliminated with an apparent half-life of 17 hours. This increase in half-life, they speculated, was due to saturation of an active transport mechanism (78). Weiner et al. (79) showed that systemic administration of probenecid, which acts by competitive inhibition of weak organic acid transport, increased the intravitreal half-life of iodopyracet to 17 hours. Similar findings were reported by Barza et al. (80,81) who demonstrated that systemic administration of probenecid increased the half-life of intravitreally injected carbenicillin and cefazolin in rabbits and monkeys. 

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