Hydrolysis in vivo

Involvement of tissue esterases is documented for zomepirac glucuronide, which undergoes rapid hydrolysis in vivo in the guinea pig and rabbit [30], Co-administration of (phenylmethyl)sulfonyl fluoride (an inhibitor of esterases) dramatically decreased the apparent plasma clearance of zomepirac glucuronide, and, in other experiments, strongly increased the apparent plasma clearance of zomepirac administered as such. 

Peptides, when administered orally, are susceptible to degradation in the stomach by gastric enzymes and the proteinases of the pancreas and brush border of the small intestine. Their lifetimes in the plasma are often short due to rapid proteolysis and other metabolic processes. Early efforts were made to improve the resistance of renin inhibitors to hydrolysis in vivo by the use of blocking groups at the Eland C-terminii [39] and replacement of susceptible peptide bonds other than the renin cleavage site. Studies of SAR have shown that various N- and C-terminal groups, some based on the morpholine nucleus and derivatives of it, have a favorable effect on the duration of inhibition in the... 

Thus, unlike procaine, the analogue procainamide is not hydrolyzed in the plasma at all, the hydrolysis in vivo being carried out by enzymes in other tissues (Fig. 4.43). 

Carbamates also include pesticides such as Sevin, aldicarb, and carbaryl. They are more degradable than organophosphates and have lower dermal toxicides. Their toxicity is also due to inhibition of acetylcholinesterase but they do not penetrate the central nervous system, so most effects are respiratory in nature. An acetylcholinesterase, which has been carbamylated can undergo spontaneous hydrolysis in vivo, which reactivates the enzyme leading to less severe symptoms or a shorter duration of symptoms. Carbaryl has a low toxicity for mammals however, Perimicarb is highly toxic to mammals, but not readily absorbed through the skin. 

Acetylated cottonseed protein demonstrated significantly higher water and oil holding capacities and improved foaming properties (38) compared to unmodified proteins (Table III). Thus, while acetylation does not significantly enhance functional properties of proteins, it improves thermal stability and since acetylated proteins are susceptible to enzyme hydrolysis in vivo it affords a useful reagent for protection of e-NH groups of lysine (11). 

Pivaloyloxymethyl (Pom) esters are useful as prodrugs of penicillin and other 0-lactam antibiotics owing to their easy hydrolysis in vivo by ubiquitous non-specific esterases. Mascaretti and co-workers showed that Pom esters can also by cleaved under mild conditions with 2 equivalents of bis(tri-/i-butyltin)oxide as shown in Scheme 6.32. The intermediate tributylstannyl esters are readily hydrolysed on treatment with water to release the carboxylic acid. Functional groups such as aldehydes, thioacetals, amides, vinyl bromides, and nitro compounds are compatible.22... 

The similarities between Ga, In and Fe " are manifest in vivo by the binding of all three ions to the serum protein transferrin, Tf, normally used for iron transpQit. The formation constant for the Ga -Tf complex has been found to be and Welch has calculated values for the equilibrium constants for the exchange of trivalent metal ions between EDTA or DTPA and Tf as shown in Table 19. These figures show that only the DTPA complex of Ga is stable with respect to metal exchange with Tf. Table 19 also shows values for the equilibrium exchange reaction between Tf and hydroxide ion. These indicate that, while the indium-Tf complex should be stable to hydrolysis in vivo, in the long term the insoluble Ga(OH)3 should form from the... 

The aromatic hydroxyl group has to he free or esterified. Blocking of the hydroxyl group as an ether inactivates the molecule. It is possible that the esters are actually inactive but undergo hydrolysis in vivo to the free phenols. Thus, delta-1-THC acetate, when tested in vitro, shows negligible activity in biochemical reactions in which delta-1-THC is active (Baneijee et al. 1975). 

Carbolines jS-CCM (14), ZR 93426 (12), and FC 7742 (18). Direct injection of the BzR inverse agonist jS-CCM (14) into the rat NBM enhanced performance in a two-trial recognition task (232), similar to the positive effects observed earlier for the peripheral administration of the same agent (233).Further development of /3-CCM (14) and DMCM (16) was never considered because of their rapid esterase-mediated hydrolysis in vivo, poor solubility even as HCl salts, and toxicity (166,234). 

The low aqueous solubility of the antibiotic clindamycin hydrochloride is responsible for the pain experienced on intramuscular injection. Phosphorylation improves the aqueous solubility from 3 to >150mg/mL and avoids the pain resulting from injection of the parent clindamycin. The phosphorylated drug (Figure 41.13) possesses little or no intrinsic antibacterial activity, but, due to the enzymatic action of phosphatases, it is rapidly converted to the parent drug. The half-life for hydrolysis in vivo is approximately lOmin and only 1-2% of an intravenous dose is eliminated in the urine as unchanged prodrug. " ... 

The foregoing studies have dealt chiefly with model substrates in vitro. Several of the early papers by Augustinsson, referred to in Section 4.1.1, considered substrate specificity from the viewpoint of species variations. It is also important to recognize that plasma cholinesterase may be associated with the hydrolysis, in vivo, of a large number of drugs (K4, LI, L4) that contain ester bonds susceptible to enzymic hydrolysis. Apart from succinylcholine (Section 3.1), cholinesterase is known to be responsible in man for the hydrolysis of cocaine (S40), procaine (K2), and other esters with local anesthetic properties. Whether enzymatic hydrolysis terminates the pharmacologic effect depends on the whole mechanism of action of the particular drug. 

The further development and clinical application of DNA vaccines are hampered by serious limitations. DNA vaccines based on naked DNA plasmids are weak immunogens, due to a number of reasons. DNA molecules without protection are quickly degraded by nucleases or hydrolysis in vivo. 

It is quite possible that the phenolic esters are also inactive as such but undergo hydrolysis in vivo to the free phenol. When tested in vitro in some biochemical reactions (in which the free phenols are active) the esters show complete lack of activity [81]. Replacement of the phenolic group by an amino group in some cannabinoids retains activity replacement by a thiol group in all cases tested so far eliminates activity [82]. 

Procaine (novocain), the first synthetic local anesthetic, is an amino ester (see Figure 14-1) with low potency, slow onset, and short duration of action. Its use now is confined to infiltration anesthesia and occasionally for diagnostic nerve blocks. Its hydrolysis in vivo produces para-aminobenzoic acid which inhibits the action of sulfonamides. Thus, large doses should not be administered to patients taking sulfonamide drugs. 

With the exception of captopril and lisinopril, ACE inhibitors are not well absorbed orally and are administered as esters (prodrugs enalapril, cilazapril, etc.) which undergo hydrolysis in vivo to release the active drugs [110]. 

More recently, camptothecin (CPT) was conjugated to poly(l-hydroxymethylethylene hydroxymethylformyl) (PHF or Eleximer ) and the conjugate 11 (XMT-1001) is currently in clinical development [72,73]. The polyacetal is derived from the exhaustive oxidation of dextran [74]. CPT is poorly soluble and prone to rapid inactivation through lactone ring hydrolysis in vivo [75]. As a cytotoxic compound, CPT has been used in many efforts to develop other CPT-polymer conjugates [45,76,77]. The sodium salt of CPT has also been examined in phase I trials, but only modest responses were observed while severe toxicities remain. 

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