Monohydroxylated metabolites

The mean oral bioavailability of finasteride is 65%, as shown in Table 45.4, and is not affected by food (99). Approximately 90% of circulating finasteride is bound to plasma proteins. Finasteride has been found to cross the blood-brain barrier, but levels in semen were undetectable (<0.2 ng/mL). Finasteride is extensively metabolized in the liver, primarily via CYP3A4 to two major metabolites monohydroxylation of the t-butyl side chain, which is further metabolized via an aldehyde intermediate to the second metabolite, a monocarboxylic acid (Fig. 45.15). The metabolites show approximately 20% the inhibition of finasteride for 5a-reductase. The mean terminal half-life is approximately 5 to 6 hours in men between 18 and 60 years of age and 8 hours in men older than 70 years of age. Following an oral dose of finasteride, approximately 40% of the dose was excreted in the urine as metabolites and approximately 57% in the feces. Even though the elimination rate of finasteride is decreased in the elderly, no dosage adjustment is necessary. No dosage adjustment is necessary in patients with renal insufficiency. A decrease in the urinary excretion of metabolites was observed in patients with renal impairment, but this was compensated for by... 

The RICs for m/z 614, indicating unchanged Indinavir, and m/z 630 and 646, i.e. those expected from its mono- and dihydroxymetabolites, are shown in Figure 5.41. This allows the presence of three monohydroxylated and one dihy-droxylated metabolite to be demonstrated the other responses observed were shown by the authors not to be associated with the drug. The MS-MS spectrum of the molecular species of the dihydroxylated compound did not allow its structure to be determined but those from the molecular species from the monohydroxylated compounds allowed the structures shown in Figure 5.42 to be proposed and these correlate well with the findings from other laboratories . 

A good example of metabolite screening as part of a discovery PK study was reported by Tiller and Romanyshyn.123 They described a dog PK study in which a monohydroxylated metabolite was found at much higher levels than the dosed NCE it was active and fit the pharmacodynamic (PD) profile better than the dosed NCE. 

The metabolism of chlorexolone to three monohydroxylated derivatives (all apparently substituted in the cyclohexane ring) in both dog and man has been reported [334]. No storage in body tissues could be detected and elimination via the kidney appeared to follow oxidation to the polar metabolites (no unchanged drug could be recovered from urine). These findings contrast with those relating to thiazides which often appear unchanged in urine. 

In rabbits, metabolism of 2-bromobiphenyl yielded two polar metabolites, one metabolite was identified as 2 -bromo-4-biphenylol (1% of the dose), and the other metabolite (traces) was also a monohydroxylated derivative, but the position of the hydroxyl group was not determined (Kohli et al. 1978). 

The full-scan BPC obtained from LTQ-FTICR LC-MS data does not display diclofenac or its monohydroxyl metabolite (Ml) that were spiked into rat bile sample due to the significant interference from ions of endogenous components in the bile (Fig. 6.9a). In contrast, MDF analysis of the LC-MS data file completely removed these interfering ions, resulting in a BPC that clearly exhibits only the drug and Ml (Fig. 6.9b). The same bile sample was analyzed with NLS and PIS using a triple-quadmpole instrument. Diclofenac lost a neutral fragment (46 Da) to form a major ion at m/z 250 under CID conditions (Fig. 6.8a). 

According to the assumed pathway for the biotransformation of cyclosporin A [43], the monohydroxylated compounds [8 -hydroxy-MeBmt ]-cyclosporin A and [4 -hydroxy-MeLeu4]cyclosporin A as well as the. iV-demethylated [Leu4]cyclosporin A are considered as the primary metabolites. Further oxidation of these substrates produces several dihydroxy and additional iV-demethyl derivatives. Recently, an acidic compound was isolated from rabbit and human bile. In this metabolite, the terminal methyl group of... 

FIGURE 7.34 ESI-MS results from the incubation of imipramine with human liver microsomes in a Zeonor (cyclic olefin copolymer) chip. A monolithic SPE column was integrated for sample cleanup (desalting and removal of enzyme) and preconcentration of the N-demethylated monohydroxylated metabolites. The data were acquired in the m/z range of 250-350. The mass spectrum shows the remaining parent drug imipramine (m/z = 281.2, 1.43 x 106 cps), the formation of the monohydroxylated isomeric metabolites of imipramine (m/z = 291.2, 1.6 x 105 cps), and the formation of the N-demethylated monohydroxylated metabolite, desipramine (m/z = 267.2, 3.2 x 104 cps) [217]. Reprinted with permission from the American Chemical Society. 

The monohydroxylated metabolites had large retention volumes (> 15 ml) on the normal phase column when 20% chloroform in heptane was the solvent and could be completely separated from tetrahydrocannabinol on this system. They were resolved from each other with a more polar solvent, 80% chloroform in heptane. 

This was interesting because there are several monohydroxylic metabolites of A9-THC. If we were monitoring, say, the molecular ion, we would detect all of these metabolites. Since 327 results from a loss of C-ll, this ion is specific for the derivative of ll-hydroxy-A9-THC. This is probably a minor point, because the various monohydroxylated metabolites have been shown to be separable by gas chromatography. Nevertheless, it does result in a highly specific determination for the most debated metabolite. 

Following chronic oral doses of 100 to 400 mg daily to 14 subjects, minimum steady-state plasma-perhexiline concentrations of 0.35 to 2.8 pg/ml (mean 1.07) were reported steady-state plasma concentrations of the major monohydroxylated metabolite ranged from 1.25 to 7.4 pg/ml (mean 3.8). Steady-state plasma concentrations in 13 subjects who had been receiving similar daily doses but had developed toxic effects were ... 

As with other organochlorine cyclodiene compounds, chlordane is metabolized mainly by the liver microsomal cytochrome P-450 system. Several metabolites are produced including chlordene chlor-ohydrin, monohydroxylated dihydrochlordene, oxy-chlordane, and relatively smaller but similar amounts of 1,2-dichlorochlordene, l-hydroxy-2-chloro-chlordene, l-hydroxy-2-chloro-2,3-epoxychlordene,... 

Hydroxy THCs, which are major metabolites, are very potent cannabimimetics. Monohydroxylation on other position of the terpene ring also usually leads to active derivatives. Dihydroxylation generally causes loss of activity. Further oxidation of the C-7 hydroxyl group to a carboxyl group causes inactivation. 

Jordan VC, Collins MM, Rowsby L, et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol I977 75(2) 305—16. 

The enantiomers of MQ and its five major monohydroxylated metabolites were analyzed by chiral capillary electrophoresis using acidic conditions and hydroxypropyl-p-cyclodextrin as buffer additive (01EL3270, 01MI96, 03EL2598, 03EL4078). 

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