The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine. Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 microg/L.

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:In vivo metabolism of tibolone was studied in three healthy postmenopausal volunteers after daily oral administration of 2.5 mg of tibolone for 5 days and a single dose of 2.5 mg Х 555 kBq of Tibolone [(7␣,17␣)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is a tissue-specific compound with favorable effects on bone, vagina, climacteric symptoms, mood, and sexual well being in postmenopausal women. It has not been observed to stimulate the endometrium (Moore, 1999) or the breast, as demonstrated by the lower incidence of breast tenderness and lower mammographic density (Valdivia and Ortega, 2000). Therefore, in some tissues, tibolone has different effects than estrogens.The metabolism of tibolone has been studied in female rats, rabbits, and dogs. A considerable number of metabolites were identified in this study using 1 H NMR and mass spectroscopy, and qualitative and quantitative differences between species were observed (Jacobs et al., 1992;Verhoeven et al., 2002). Major phase I metabolic routes were the reduction of 3-keto to 3␣-or 3␤-hydroxy moieties, and the major phase II metabolic route was sulfate conjugation of the hydroxy groups at C3 and C17. Profiling of the target organs showed a tissue-specific distribution of metabolites. The majority of these metabolites existed as sulfate conjugates. These data in animals indicate that tibolone exerts its tissue-specific activities, at least partly, due to its tissue-specific metabolism and distribution. In addition, the presence of local sulfatases may convert inactive sulfated metabolites to active forms.The linearity of the pharmacokinetic profile of tibolone was studied in three groups of nine healthy female volunteers using 1.25, 2.5, and 5 mg of tibolone, respectively. The pharmacokinetic profile was mainly based on the primary phase I plasma metabolites (i.e., tibolone, 3␣-hydroxy tibolone, 3␤-hydroxy tibolone, and ⌬ 4 -tibolone). The steady state was attained by day 5 in all three dose groups. Since in most cases the plasma concentration of tibolone and ⌬ 4 -tibolone was below the detection limit, their elimination half-life could not reliably be determined. The geometric mean value of the elimination half-life of 3␣-hydroxy tibolone for the three dose levels ranged from 7.2 to 8.5 h. The very low plasma concentrations of the parent compound and the even lower concentrations of the ⌬ 4 -isomer, in combination with the considerably higher concentrations of the 3␣-and 3␤-hydroxy metabolites, indicated that tibolone is extensively metabolized, predominantly by hydroxylation at C3.Human biotransformation pathways need to be identified, and the possibility of metabolic or pharmacokinetic interactions occurring with coadministered compounds need to be addressed during the development of a drug. In vitro approaches are usually used to study these issues and to evaluate their potential clinical relevance. These in vitro studies generally focus on cytochrome P450, which is a collecti...

This paper investigated the pharmacokinetics and biotransformation of mirtazapine in healthy human volunteers. The results showed that the area under the plasma drug concentration-time curve (AUC) of mirtazapine in human plasma appeared to be three times higher than the AUC of demethylmirtazapine. As mirtazapine is marketed as a racemic mixture and both enantiomers possess pharmacological properties essential for the overall activity of the racemate, the pharmacokinetics of mirtazapine were examined and appeared to be enantioselective. The R(-)-enantiomer showed the longest elimination half-life from plasma. This was ascribed to the preferred formation of a quaternary ammonium glucuronide of the R(-)-enantiomer. This glucuronide may be deconjugated, leading to a further circulation of the parent compound, thus causing a prolongation in the elimination half-life. The S(+)-enantiomer was preferentially metabolised into an 8-hydroxy glucuronide. Other metabolic transformation pathways found for mirtazapine were demethylation and N-oxidation. Mirtazapine was extensively metabolised and almost completely excreted in the urine (over 80%) and faeces within a few days after oral administration.

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