The effectiveness of dentifrices without and with sodium lauryl sulfate on plaque, gingivitis and gingival abrasion--a randomized clinical trial.

OBJECTIVES: The aim of this study was to compare the efficacy of a dentifrice without sodium lauryl sulfate (SLS) to a dentifrice with SLS in young adults aged 18-34 years on gingivitis. MATERIAL AND METHODS: One hundred twenty participants (non-dental students) with a moderate gingival inflammation (bleeding on probing at 40-70 % of test sites) were included in this randomized controlled double blind clinical trial. According to randomization, participants had to brush their teeth either with dentifrice without SLS or with SLS for 8 weeks. The primary outcome was bleeding on marginal probing (BOMP). The secondary outcomes were plaque scores and gingival abrasion scores (GA) as well as a visual analogue scale (VAS) score at exit survey. Baseline and end differences were analysed by univariate analysis of covariance (ANCOVA) test, between group differences by independent t test and within groups by paired sample t test. RESULTS: BOMP improved within groups from on average 0.80 at baseline to 0.60 in the group without SLS and to 0.56 in the group with SLS. No statistical difference for BOMP, plaque and gingival abrasion was found between both groups. VAS scores for taste, freshness and foaming effect were significantly in favour of the SLS-containing dentifrice. CONCLUSION: The test dentifrice without SLS was as effective as a regular SLS dentifrice on gingival bleeding scores and plaque scores. There was no significant difference in the incidence of gingival abrasion. CLINICAL RELEVANCE: In patients diagnosed with gingivitis, a dentifrice without SLS seems to be equally effective compared to a dentifrice with SLS and did not demonstrate any significant difference in gingival abrasion. In patient with recurrent aphthous ulcers, the absence of SLS may even be beneficial. However, participants indicate that they appreciate the foaming effect of a dentifrice with SLS more.

Reduction of erosion by protein-containing toothpastes.

AIM: To assess the effect of protein-containing toothpastes on the progression of dental erosion in situ (with pellicle) and in vitro (without pellicle). METHODS: A combined split-mouth (extraoral water or toothpaste brushing) and crossover (type of toothpaste) setup was used. Two protein-containing (high/low concentrations of colostrum) and one nonprotein (placebo) toothpaste were investigated. Sixteen volunteers wore intraoral appliances containing 2 human enamel samples on 3 afternoons for pellicle growth during 90 min. One enamel sample was brushed for 5 s with one of the three toothpastes and subsequently exposed to a slurry of the corresponding toothpaste for 2 min. The other sample was exposed to water. Both samples were subsequently exposed to citric acid (extraorally). Loss of calcium and inorganic phosphate were determined. The same sequence of exposures was applied to 16 enamel samples in an in vitro setup without pellicle. RESULTS: With the in situ-formed pellicle, all toothpastes significantly reduced calcium loss compared to water brushing, although no significant differences were found among toothpastes (p = 0.073). For the loss of phosphate, a significant reduction could be found with the use of the high-protein toothpaste compared to the nonprotein toothpaste. Overall there were only slight differences between the toothpastes. Toothpaste effects were less clear in the in vitro experiment. CONCLUSION: The addition of proteins to toothpaste shows some promise for the prevention of erosion. Further research is needed to investigate the performance of the protein-containing toothpastes in longer in situ studies with regard to erosive wear.

Pharmacokinetic parameters of sulfated tibolone metabolites in postmenopausal women after single and multiple doses of tibolone.

The objective of this study was to determine pharmacokinetic parameters of sulfated tibolone metabolites after single dose and their accumulation after multiple doses of tibolone. Blood samples from postmenopausal women in a single-dose (2.5 mg tibolone), open-label study (n=8) and multiple-dose (placebo, 0.3, 0.625, 1.25, or 2.5 mg/day tibolone for twenty-six cycles of 28 days), randomized, double-blind study (n=15) were analyzed for non-sulfated and sulfated tibolone metabolites by validated gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tanolam mass spectrometry (LC-MS/MS), respectively. The predominant non-sulfated and sulfated metabolites after a single dose were 3alpha-hydroxy-tibolone and 3alpha,17beta-di-sulfated (di-S)-tibolone. At 3 h, >90% of metabolites were sulfated. Tibolone and Delta(4)-tibolone were detectable for about 6 h. After multiple treatment cycles with different doses, metabolite levels at 10 h were dose-related and levels of di-S metabolites were three- to fivefold higher than after a single dose. Tibolone metabolite levels did not differ between cycles. Inactive di-S tibolone metabolites predominated in blood. No accumulation occurred between cycles 7 and 26.

Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring.

OBJECTIVE: To assess the pharmacokinetics of etonogestrel and ethinylestradiol released from a novel combined contraceptive vaginal ring (NuvaRing) releasing etonogestrel 120microg and ethinylestradiol 15 microg per day and compare them with those of a combined oral contraceptive containing desogestrel 150 microg/ethinylestradiol 30 microg (DSG/EE COC). DESIGN AND SETTING: This was a nonblind, randomised, crossover study in 16 healthy women. METHODS: All volunteers received one cycle of DSG/EE COC before being randomised to 1 of 2 treatment groups. The participants in group 1 received 1 cycle of DSG/EE COC, a treatment period with NuvaRing and an intravenous bolus injection of etonogestrel/ethinylestradiol (150 microg/30 microg). Those in group 2 received a NuvaRing treatment period, 1 cycle of DSG/EE COC and the same intravenous bolus injection. RESULTS AND CONCLUSIONS: After the insertion of NuvaRing, maximum serum concentrations of etonogestrel and ethinylestradiol were achieved in approximately 1 week. The concentrations subsequently showed a gradual linear decrease in time. The maximum serum concentrations of etonogestrel and ethinylestradiol were approximately 40 and 30%, respectively, of those for the DSG/EE COC. In comparison with the DSG/EE COC, the absolute bioavailability for NuvaRing was higher for etonogestrel (102.9 vs 79.2%) and similar for ethinylestradiol (55.6 vs 53.8%). Taking the difference in daily doses into account, systemic exposure to etonogestrel was similar for NuvaRing and the DSG/EE COC, whereas systemic exposure to ethinylestradiol with NuvaRing was only approximately 50% of that for the DSG/EE COC.

Clinical pharmacokinetics of mirtazapine.

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.

Pharmacokinetics of a triphasic oral contraceptive containing desogestrel and ethinyl estradiol.

OBJECTIVE: To demonstrate that pharmacokinetic measurements were made at steady state. Subsequently, dose proportionality for desogestrel and ethinyl E2 kinetics were demonstrated. DESIGN: Open-label, noncomparative study. SETTING: Healthy volunteers in an academic research environment. PARTICIPANTS: Twenty white women who were 19 to 32 years old were solicited via an advertisement. Nineteen of the 20 women completed the study. INTERVENTIONS: Study medication consisted of three cycles of a triphasic oral contraceptive containing desogestrel and ethinyl E2. Blood samples were taken at baseline and during cycle 3 between -48 and 24 hours on days 1, 7, 14, and 21, with additional sampling times on day 21 at 48, 60, and 72 hours. MAIN OUTCOME MEASURES: Serum concentrations of 3-keto-desogestrel and ethinyl E2. RESULTS: Evaluation of the trough serum levels indicated that a steady state of 3-keto-desogestrel had been reached. Statistical analysis on the Cmax, area under the curve (AUC), and Css,min indicated dose proportionality for the administered desogestrel. Ethinyl E2 serum levels obtained at the same time points also reflected steady state levels and showed minimal variability. The statistical analysis on Cmax, AUC, Css,min, and Tmax indicated that the pharmacokinetics of ethinyl E2 on days 7, 14, and 21 were not statistically significantly different, indicating dose equivalency. CONCLUSIONS: Steady state of 3-keto-desogestrel is reached after each of the three phases and the pharmacokinetics are dose proportional. After reaching steady state, the pharmacokinetics of ethinyl E2 remain constant over time.

PIP: This article presents the results of an open-label, noncomparative study analyzing the effects of three different combinations of a triphasic oral contraceptive (OC) containing desogestrel and ethinyl estradiol (ethinyl E2) in 20 healthy White female volunteers. Each study subject was required to pass a physical examination, which included Papanicolaou smear, serological analysis, and urinalysis. The mean age of the study group was 25.1 years. The mean body weight was 143.0 pounds (64.9 kg). The study administration series consisted of tablets containing three combinations of desogestrel and ethinyl E2 (desogestrel/ethinyl E2: 50/35 mcg, 100/30 mcg, and 150/30 mcg). The dosage schedule was 7/7/7, that is, a different dose for each 7-day period. This was followed by a 7-day medication-free period to reflect a 28-day cycle. Venous blood was taken and analyzed for 3-keto-desogestrel, ethinyl E2, and sex hormone-binding globulin (SHBG). This was performed for 3 menstrual-equivalent cycles. Evaluation of the serum levels for 3-keto-desogestrel was proportional to each combined OC dosage. This was also true for ethinyl E2. Dose equivalency was indicated for ethinyl E2, as the three dosage regimens were not different or statistically significant. In this study, use of a triphasic oral contraceptive containing desogestrel and ethinyl E2 resulted in a statistically significant increase in SHBG serum levels between cycle day 7 and 21 (185.5 +or- 32.1 vs. 205.6 +or- 21.9 mmol/L).

Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part I. Absolute bioavailability of 0.25 mg of ganirelix after a single subcutaneous injection in healthy female volunteers.

OBJECTIVE: To assess the absolute bioavailability of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC injection. DESIGN: Randomized, crossover, pharmacokinetic study. SETTING: Phase I clinical research unit. PATIENT(S): Nineteen healthy female volunteers of reproductive age. INTERVENTION(S): Two separate injections of 0.25 mg of ganirelix were given, one subcutaneously and one intravenously, with a washout period of 1 week between injections. Blood samples were taken for assessment of serum ganirelix concentrations, and blood pressure, heart rate, and adverse events were monitored. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULT(S): Fifteen subjects were evaluated. The mean concentration-time profile after SC administration was comparable to that after IV administration. The mean (+/- SD) peak concentration and time of occurrence after SC administration were 14.8+/-3.2 ng/mL and 1.1+/-0.3 hours, respectively. The mean (+/- SD) half-lives after IV administration and SC administration were highly similar (12.7+/-3.7 hours and 12.8+/-4.3 hours, respectively). Mean (+/- SD) AUC0-infinity (area under the concentration-time curve) values of 105+/-11 ng/mL x hours and 96+/-12 ng/mL x hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean (+/- SD) bioavailability of 91.3%+/-6.7%. Both treatments were well tolerated. CONCLUSION(S): Ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of >90%.

Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part II. Dose-proportionality and gonadotropin suppression after multiple doses of ganirelix in healthy female volunteers.

OBJECTIVE: To assess the dose-proportionality and pharmacodynamic properties of multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands). DESIGN: Randomized, parallel, pharmacokinetic, and pharmacodynamic study. SETTING: Phase I clinical research unit. PATIENT(S): Three groups of 15 healthy female volunteers of reproductive age. INTERVENTION(S): Subcutaneous injections of 0.125 mg, 0.25 mg, or 0.50 mg of ganirelix were given once daily for 7 days. Blood samples were taken to assess serum ganirelix, LH, FSH, and E2 concentrations. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters and hormone suppression. RESULT(S): Steady-state levels were reached between days 2 and 3. Peak concentrations, which occurred approximately 1 hour after dosing, increased in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/mL for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Corresponding mean values for the area under the curve over one dosing interval (24 hours) were 33 ng x h/mL, 77.1 ng x h/mL, and 137.8 ng x h/mL, respectively. After the last 0.25-mg dose of ganirelix, serum LH, FSH, and E2 concentrations were maximally decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 hours after injection, respectively). Serum hormone levels returned to pretreatment values within 2 days after the last injection. CONCLUSION(S): The pharmacokinetics of ganirelix were dose-proportional within the dose range studied. Multiple injections resulted in immediate suppression of gonadotropins, which was rapidly reversed after treatment discontinuation.

Pharmacokinetics of mirtazapine and lithium in healthy male subjects.

A substantial proportion of patients diagnosed with depression and treated with antidepressants show no or insufficient response. In such patients, lithium is often added to the antidepressant for augmentation. The present study investigated the possible drug-drug interaction between mirtazapine and lithium in 12 healthy male subjects in a randomized, double-blind, placebo-controlled two-period cross-over design. Subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups. After an overnight fast, they received either a single oral dose of 600 mg lithium carbonate (16 meq Li+) for 10 days at 08.00 h and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9 or the same number (n = 4) of placebo capsules and and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9. At pre-defined times, blood samples were drawn for the measurement of mirtazapine plasma concentrations and lithium serum concentrations. In addition, psychometric tests were performed and the safety and tolerability of the drugs were assessed. The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively.

Pharmacokinetic evaluation of gepirone immediate-release capsules and gepirone extended-release tablets in healthy volunteers.

In an open-label, randomized, crossover study, the pharmacokinetics of gepirone immediate-release (gepirone-IR) and different gepirone extended-release (gepirone-ER, types 1, 2, and 3) formulations were compared. Mean maximum concentration (C(max)) was 6.1 ng/mL for gepirone-IR, which was statistically significantly (p < 0.05) higher than that of two of the ER-formulations (3.7 and 3.6 ng/mL, respectively, for types 2 and 3). The mean time to C(max) (mean T(max)) was 1.3 h for gepirone-IR and ranged from 4.8 to 5.6 h for gepirone-ER. The mean area under the curve of concentration versus time (AUC(30)) was similar and not statistically significantly different between gepirone-IR and ER. For the 1-(2-pyrimidinyl)-piperazine (1-PP) metabolite, C(max) and AUC(30) were statistically significantly (p < 0.05) higher and T(max) was lower for gepirone-IR compared with ER. No significant differences in bioavailability were observed between the IR and the three gepirone-ER formulations, indicating that any of the once-daily gepirone-ER formulations could be substituted for gepirone-IR. This study revealed a reduction in the peak-to-trough fluctuations in plasma gepirone concentrations and maintenance of consistent plasma levels with gepirone-ER.

Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from different types of contraceptive vaginal rings.

Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from contraceptive vaginal rings (CVRs) with different release rates (75/15, 100/15 and 150/15 micrograms 3-keto-desogestrel/ethinylestradiol daily) were investigated in two studies in young healthy female volunteers. As reference, an oral preparation containing 150 micrograms desogestrel and 30 micrograms ethinylestradiol (MarvelonR tablets) was also administered to the volunteers. To assess the disposition parameters of 3-keto-desogestrel and ethinylestradiol, some of the volunteers were additionally given an i.v. preparation containing 150 micrograms 3-keto-desogestrel and 30 micrograms ethinylestradiol. Serum levels obtained with CVRs showed an initial increase during the first three days, followed by a plateau decreasing only slightly during the remainder of the treatment period. Mean plateau levels (+/- s.d.) of 3-keto-desogestrel were 2.3 +/- 0.9, 2.8 +/- 1.1 and 3.8 +/- 1.1 pmol/ml for CVR 75/15, 100/15 and 150/15, respectively. Mean plateau levels of ethinylestradiol were 184 +/- 75, 262 +/- 102 and 233 +/- 102 pmol/l, respectively. The in vivo release rates of 3-keto-desogestrel and ethinylestradiol from the CVRs were in good agreement with the in vitro release rates. For both steroids the bioavailability from the CVRs was approximately 1.2 times higher than that from the tablets. The 3-keto-desogestrel serum levels were found directly proportional to the release rates within the range studied (75-150 micrograms/day). For ethinylesteradiol the intra-individual variation in steady-state levels was too large to draw pertinent conclusions.

Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women.

The pharmacokinetics and enterohepatic cycling of oestradiol have been studied after three oral, single-dose administrations of equimolar doses of oestradiol alone, oestradiol plus desogestrel and oestradiol valerate, in a 3-way cross-over mode in 18 healthy postmenopausal women. Oestradiol was readily absorbed and metabolized to oestrone, which reached much higher serum concentrations (140pgmL(-1)) than its parent compound (35pgmL(-1)). All three formulations had the same kinetic profile and were bioequivalent on testing. Noticeable first and second absorption phases were apparent from the oestradiol and oestrone serum concentration-time curves for all oestradiol formulations. The mean serum concentration-time curves of the metabolite oestrone (corrected for endogenous oestrone) showed a second maximum at approximately 25h. By means of line feathering, serum concentration-time curves were constructed which belonged to the first, second and third phases of absorption. The maximum serum concentration, Cmax, of the second absorption or recirculation of oestrone was 20% that of the first, and the Cmax of the third circulation was 50% that of the second. The areas under the serum-concentration-time curves (AUC) for the second and third recirculations were similar-each comprised 12-13% of the total AUC. The oral clearance values of the recirculations were constant (590Lh(-1)). Enterohepatic recirculation of endogenous compounds is aimed at maintaining a steady-state serum concentration for immediate use and hydrolysis in the target organs. It is concluded that exogenously added oestradiol and its metabolites follow the recirculation pathways of the endogenous oestrogen pool.

Pharmacokinetics and biotransformation of mirtazapine in human volunteers.

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.

Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomized, single-dose, 3-way cross-over study.

OBJECTIVE: The aim of the study was to assess the bioavailability of estradiol (E2) following oral, single-dose administration of equimolar doses of three HRT preparations in a 3-way cross-over study in postmenopausal women. METHODS: 18 healthy subjects were enrolled. Free E2 and estrone (E1) serum concentrations were determined using commercially available immunoassay kits. Bioequivalence testing was performed between the following oral formulations: (a) 1.5 mg E2 tablets versus 2 mg E2V tablets; and (b) 1.5 mg E2 plus 0.15 mg DSG tablets versus 1.5 mg E2 tablets. RESULTS: For both E2 and E1 the E2 tablet was bioequivalent with both the E2V and the E2/DSG tablet with respect to the rate and extent of absorption (bioavailability). Although the mean tmax values of the three tablet formulations were similar, the variability was too large to prove formal bioequivalence. CONCLUSION: E2 tablets and E2/DSG tablets were bioequivalent and also bioequivalence of E2 tablets with commercially available E2V was found, which ensures a sequential HRT preparation without large variations in estrogen serum concentrations.

Pharmacokinetics of mirtazapine from orally administered tablets: influence of a high-fat meal.

The effect of a high-fat meal on the pharmacokinetics of mirtazapine was studied in 19 healthy normal young male volunteers. In a randomized two-period crossover study, each volunteer received an oral dose of 15 mg of mirtazapine in the form of tablets, in the fasting state and after a high-fat meal, with a washout period of 14 days between the two doses. Serial blood samples were taken and pharmacokinetic parameters calculated and statistically analyzed from mirtazapine plasma levels. The extent of absorption of mirtazapine, as measured by the area under the plasma level versus time curve, was found to be equivalent for the fasting and the fed state. Food intake was shown to have no influence on the elimination of mirtazapine, as measured by its elimination half-life. The rate of mirtazapine absorption, as measured by the peak level (Cmax), was not altered by food. The peak time (tmax), however, in subjects in the fed state showed an increase: the 90%-confidence interval for the median difference ranged from 0.25 to 1.25 h. This was the only effect of food found in this study. It is considered to be of no clinical consequence.

Bioavailability and bioequivalence of etonogestrel from two oral formulations of desogestrel: Cerazette and Liseta.

In a three-period cross-over study with 24 healthy young females (study part 1), the bioavailability of etonogestrel (3-ketodesogestrel) was determined after a single oral dose of two Cerazette tablets (each containing 75 microg desogestrel), one Liseta tablet (containing 150 microg desogestrel and 1.5 mg 17beta-estradiol), and an intravenous dose of 150 microg etonogestrel. Etonogestrel serum levels from 23 subjects could be analysed by radio-immunoassay. The geometric mean bioavailability of etonogestrel from Cerazette and Liseta tablets was 0.79 and 0.82, with 95% confidence intervals of 0.73-0.86 and 0.76-0.88, respectively. Also, the oral formulations were found to be bioequivalent. Subsequently, the single-dose pharmacokinetic parameters of etonogestrel from Cerazette tablets were compared with those after multiple dosing of one Cerazette tablet once daily for 7 days, in a subgroup of 12 subjects (study part 2). A steady state was observed from the fourth day of daily dosing onwards, with time-invariant parameters except for a 14% lower dose-normalised AUC. The least-squares geometric means of the elimination half-life of etonogestrel were approximately 30 h for the three single-dose treatments in study part 1, as well as for the single- and multiple-dose treatments of Cerazette in study part 2, without differences between groups.

Absolute bioavailability of mianserin tablets and solution in healthy humans.

A pharmacokinetic study with mianserin . HCl was performed in six healthy male subjects. The subjects were treated on different occasions intravenously with a constant-rate infusion of 5 mg mianserin. HCl in 1 h, orally with a single dose of 60 mg as two tablets of 30 mg each and with 60 mg as an oral solution. The wash-out period between treatments was 1 month. Blood samples were taken at predetermined times over a period of 120 h following dosing. The mianserin concentration in the plasma samples was determined and the results were pharmacokinetically analyzed. The intravenous data could be adequately described by a 3-compartment model and the oral data by a 2-compartment model, both with first-order transfer and elimination rate constants. The mean plasma clearance of mianserin was found to be 19 +/- 2 l h-1 (mean +/- SEM), the kinetic volume of distribution 444 +/- 250 l, the steady-state volume of distribution 242 +/- 171 l and the elimination half-life 33 +/- 5 h. The absolute bioavailability in terms of extent of absorption was 22 +/- 3% for the solution and 20 +/- 3% for the tablets. The mean peak level for the solution was 79 +/- 11 ng X ml-1 and for the tablets 54 +/- 5 ng X ml-1; mean peak time for the solution was 1.1 +/- 0.2 h and for the tablets 1.4 +/- 0.2 h. The mean absorption half-life for the solution was 0.43 +/- 0.13 h and for the tablets 0.39 +/- 0.11 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces, and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone.

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.