Metabolic inactivation

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

The complete role of N,N-dialkyl substitution is not fully understood, although it serves to enhance blood-brain barrier permeability and to hinder metabolic inactivation. 

Figure 4. Proposed scheme for Cytochrome P-450 mediated metabolism (inactivation and activation) of procarcinogens (e.g. PAHs).

Fujii H, Sato T, Kaneko S, Gotoh O, Fujii-Kuriyama Y, et al. 1997. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO J 16 4163-4173. 

The plasma half-fife of an intravenous bolus injection of mercaptopurine is 21 minutes in children and 47 minutes in adults. After oral administration, peak plasma levels are attained within 2 hours. The drug is 20% bound to plasma proteins and does not enter the CSF. Xanthine oxidase is the primary enzyme involved in the metabolic inactivation of mercaptopurine. 

Mulder GJ. Drug metabolism inactivation and bioactivation of xenobiotics. In Mulder GJ, Dencker L, eds. Pharmaceutical Toxicology. London, UK Pharmaceutical Press, 2006. 

Drug metabolism studies including identification of bioactive metabolites and blocking of metabolic inactivation. 

Pharmacokinetic properties Intravenous alfentanil (Hull, 1983) has a rapid onset and a short duration of action. It has a shorter elimination time (terminal half-life 1-2 h) than fentanyl. It is less lipid-soluble and the short duration of action is more dependent on metabolic inactivation than on redistribution. Alfentanil has a high (90%) plasma protein binding. Metabolic inactivation is effected by oxidative N- and O-demethylation. 

Pharmacokinetic properties Butorphanol (Vachharajani et al., 1997) is rapidly inactivated by first pass metabolism in the gut. Intramuscular and nasal administration induces a peak effect between 0.5-1 hr and a duration of action of about 3 h, corresponding to the plasma half-life time of the compound. Butorphanol has a plasma protein binding of about 80%, metabolic inactivation includes hydroxylation,... 

Pharmacokinetic properties Fentanyl (Scholz et al., 1996) is a highly lipophilic compound and about 80% binds to plasma proteins. After parenteral administration it has a rapid onset and a short duration of action. The compound is rapidly transported into the CNS and lipid tissues. The short duration of action is due to redistribution rather than metabolic inactivation or excretion. It is released from tissue depots with a half-life of about 4 h and the terminal half-life is up to 7 h. The main metabolites, excreted in urine are 4-N-(N-propionylanilino)-piperidine and the N-hydroxypropionyl derivative. 

Pharmacokinetic properties The compound has an acceptable oral bioavailability (Bondesson, 1980). Metabolic inactivation occurs via N-demethylation and glucuronidation at the phenolic hydroxyl. 

Pharmacokinetic properties After oral administration levorphanol has a relatively slow onset, but a long (up to 8 h) duration of action. Metabolic inactivation occurs via glucuronidation of the phenolic hydroxyl and via N-demethylation (Dixon et al., 1983). 

The occupancy of hormone receptors can fluctuate greatly and is ultimately determined by the concentration of free hormone in the blood. The major determinants of hormone concentrations are (1) the rate of hormone secretion from endocrine cells and (2) the rate of hormone removal by clearance or metabolic inactivation. As we have seen, most hormones (with the exception of steroids) are stored in secretory granules. When the hormone is needed, the granule membranes fuse with the plasma membrane to liberate their contents into the bloodstream. This event is triggered by signals from other hormones or by neural signals. Stimulation of hormonal secretion is usually coupled with an increase of hormone synthesis, so that hormonal stores are replenished. 

The cellular effects of FTase inhibition with 3 were observed with concentrations 5000-50,000 higher than the in vitro IC50 for FTase inhibition by carboxylic acid Id. Incomplete hydrolysis of the lactone in vivo could be partially responsible for this discrepancy in activity. However, it was also found that the lactone prodrug used in the context of the doubly reduced peptide isostere, i.e. 3, was chemically unstable at physiological pH. Rapid cyclization to the diketopiperazine 5 significantly reduced FTase inhibitory activity.40 Simple N-alkylation of the reactive secondary amine to give 4 led to loss of activity vs. FTase. To simultaneously protect the compound from both metabolic inactivation (via peptidases) and chemical instability, isosteric replacements of the second amide bond other than methylene-amino were explored. Since the second amide bond in the tetrapeptide inhibitors could be reduced without loss of activity in vitro, peptide bond replacements which were both rigid (olefin) and flexible (alkyl, ether) were synthesized. 

Cotterman, J.C. and F.F. Saari (1992). Rapid metabolic inactivation is the basis for cross-resistance to chlorsulfuron in diclofop-methyl-resistant rigid ryegrass (Lolium rigidum) biotype SR4/84. Pestic. Biochem. Physiol., 43 182-192. 

Mulder, G.J., 2006, Drug metabolism Inactivation and activation of xenobiotics. In Mulder, G.J. and Dencker, L. (Eds), Pharmaceutical toxicology, Pharmaceutical Press, 41-66. 

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