Acute effects of triazolam in women: relationships with progesterone, estradiol and allopregnanolone

 This study investigated hormone levels and mood in normal women to explore relationships between levels of circulating hormones and i) baseline mood states and ii) effects of triazolam on mood. Certain ovarian hormones or their metabolites have direct actions on neuronal receptors. These actions may result in changes in mood state, or changes in responses to psychoactive drugs which act on the same receptors. The present study explored relationships between estrogen, progesterone and a metabolite of progesterone, allopregnanolone, and the mood-altering and performance effects of an acute dose of triazolam. Triazolam is a short-acting benzodiazepine which acts via the GABA_A receptor complex. Twenty women received triazolam (0.25 mg) or placebo at the follicular, ovulatory and luteal phases of their menstrual cycle. Each subject participated in six conditions (i.e., drug and placebo at each of the three phases), across two menstrual cycles. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of estradiol, progesterone, allopregnanolone, and triazolam. Mood and performance measures were not clearly related to hormone levels when data from all three phases were examined. However, within the luteal phase, higher levels of allopregnanolone were associated with lower self-reported arousal before any drug administration (i.e., at baseline). After administration of triazolam, most subjects reported the expected decreases in ratings of arousal. However, the subjects with the highest levels of allopregnanolone reported increases in ratings of arousal. Thus, hormone levels were related to mood and responses to triazolam, particularly during the luteal phase of the cycle. However, the drug-hormone interactions on mood and behavior were complex. Received: 6 March 1996/ Final version: 16 October 1996     

Modulation of the discriminative stimulus effects of triazolam across the menstrual cycle phase in healthy pre-menopausal women

Pre-clinical studies indicate that changes in progesterone levels across menstrual cycle phases modulate the behavioral effects of sedative drugs acting at GABA(A) receptor sites. In this study, seven healthy women learned to discriminate triazolam (0.25 mg/70 kg) from placebo. After acquiring the discrimination, a range of triazolam doses (0.00, 0.06, 0.12 and 0.25 mg/70 kg) was tested during the early follicular and mid-luteal menstrual cycle phases. During the mid-luteal phase, when progesterone levels were elevated, 0.12 mg/70 kg triazolam was identified as the active triazolam training dose (0.25 mg/70 kg), whereas 0.12 mg/70 kg triazolam was identified as placebo during the early follicular phase, when progesterone levels were low. Triazolam engendered prototypical sedative effects on subjective effect, performance and cardiovascular measures that were generally independent of cycle phase. These results suggest that the discriminative stimulus effects of the positive GABA(A) modulator, triazolam, are sensitive to menstrual cycle phase in healthy adult women.     

The effect of the menstrual cycle on the pharmacokinetics of caffeine in normal, healthy eumenorrheic females

  Objective: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug. Methods: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2–6 post-onset of menses), ovulatory (days 13–16 post-onset of menses) and luteal (days 22–26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method. Results: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration–time curve (AUC_inf) was 93.01 mg l^−1.h and the absorption rate constant (k _a) was 2.88 h⁻¹ during the ovulatory phase, 83.0 mg l⁻¹ h and 2.06 h⁻¹, respectively, during the luteal phase and 84.7 mg l^−1.h and 1.84 h⁻¹, respectively, during the follicular phase. Conclusions: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine. Received: 16 November 1998 / Accepted in revised form: 19 April 1999     

Effects of triazolam at three phases of the menstrual cycle.

This study investigated the subjective and behavioral effects of a commonly used benzodiazepine, triazolam, in healthy women at three phases of the menstrual cycle: follicular, periovulatory, and luteal. Ovarian hormones or their metabolites have direct and indirect actions on neuronal receptors, which may affect responses to psychoactive drugs acting on the same central nervous system receptors. This study explored the effect of menstrual cycle phase on the mood-altering and performance effects of a single oral dose of the benzodiazepine triazolam. Twenty women received triazolam (0.25 mg orally) or placebo at the follicular, periovulatory, and luteal phases of their menstrual cycles in a within-subject design. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of triazolam, estradiol, progesterone, and allopregnanolone. After administration of triazolam, most subjects reported the expected increases in fatigue and decreases in arousal and psychomotor performance. Neither plasma levels nor mood and performance effects of triazolam differed across the three phases. This study illustrates a useful methodology for assessing responses to psychoactive drugs in normally cycling women and shows that the effects of this drug were highly stable across the cycle.     

Influence of menstrual cycle on the pharmacokinetics of paracetamol through salivary compartment in healthy subjects

Hormonal changes during the different phases of menstrual cycle may influence drug disposition. The objective of this study was to investigate the influence of the menstrual cycle on the pharmacokinetics of paracetamol through salivary compartment in young healthy Indian women (n = 12) with regular menstrual cycles. The subjects received an oral dose of 1 g paracetamol on the 3rd, 13th, and 23rd days of their menstrual cycle in a 3 x 3 randomized crossover design. Saliva samples were collected at predetermined time intervals and the paracetamol content in them was estimated using an established HPLC method. The pharmacokinetics of paracetamol was worked out using a model-independent method employing WinNonlin 3.1. The mean Cmax of paracetamol was significantly (p < 0.05) lower (31.5%) in the ovulatory phase than in the follicular phase. The mean AUC0-t and AUC0-infinity values were significantly (p < 0.05) lower in the ovulatory phase than those in the luteal phase. These changes could be due to increased first-pass metabolism and decreased bioavailability of paracetamol during the ovulatory phase.     

Comparative pharmacokinetics of paracetamol in men and women considering follicular and luteal phases

The pharmacokinetics of paracetamol administered in a single dose were investigated and compared in young male and female subjects, considering follicular and luteal phase of the menstrual cycle. The mean AUC for paracetamol in the blood of female subjects was significantly increased by 39% and 51%, respectively, taking into account the follicular and luteal phase, in comparison with the AUCs of male volunteers. The peak plasma concentration revealed significantly higher values in women in both phases, by 48% and 66%, respectively. The time to reach the peak concentration was shorter by 8% in follicular phase than in males. The difference was statistically insignificant. Elimination constant decreased in follicular phase by 15% and in luteal phase by 21% in comparison with males (the difference--statistically insignificant). The paracetamol half-life was longer (although not significantly) in women than in men: in follicular phase by 29 min, i.e. 15%, and in luteal phase by 65 min, i.e. 33%. The apparent volume of distribution was found to be significantly lower in the female group by 35% and 40% in follicular and luteal phase, respectively. Comparing data obtained in the follicular and luteal phase, it was shown that the AUC was larger, peak plasma concentration was higher and biological half-life was longer in luteal phase. It is likely that the differences in some pharmacokinetic parameters between men and women, as well as in women considering both phases of menstrual cycle, might be of clinical significance.     

Pharmacokinetics and safety of oral eletriptan during different phases of the menstrual cycle in healthy volunteers.

The purpose of this study was to determine the pharmacokinetics and safety of eletriptan in different phases of the menstrual cycle. Female volunteers (n = 16) with a regular menstrual cycle (28 +/- 4 days) received a single oral dose of 80 mg eletriptan during each of the four cycle phases: phase 1 (menses), days 1 to 4; phase 2 (follicular), days 6 to 10; phase 3 (ovulatory), days 11 to 13; and phase 4 (luteal), days 21 to 24. Eletriptan plasma concentrations were determined from serial plasma samples taken during a 24-hourperiod after dosing. Blood pressure, pulse rate, and ECG measurements were performed at baseline, 1 and 24 hours after dosing. No significant differences between phases were observed for maximum plasma concentration (cmax, range of means = 188-234 ng/ml), time to maximum concentration (tmax, range of means = 1.8-2.5 h), or systemic exposure (area under the curve [AUC], range of means = 1194-1514 ng x h/ml). Although there was a statistically significant difference in the terminal phase elimination rate constant (kel) between phases 1 and2 (0.175/h vs. 0.158/h, p = 0.044), the corresponding difference in terminal phase half-life (t 1/2) (4.0 h vs. 4.4 h) was not considered to be clinicallyrelevant. No clinically relevant differences in blood pressure, pulse rate, or ECG were observed, and the incidence, nature, and severity of adverse events were similar in all phases. The different phases of the menstrual cycle had no clinically significant effect on the pharmacokinetics, safety, or tolerability of oral 80 mg eletriptan in healthy females.     

Absence of tobramycin pharmacokinetic and creatinine clearance variation during the menstrual cycle: implied absence of variation in glomerular filtration rate

During the menstrual cycle, a 20% increase in creatinine clearance (CL(CR] has previously been reported between the menstrual (phase 1) and late luteal (phase 4) phases. Tobramycin pharmacokinetics and CL(CR) were studied in eight healthy women with documented, regular, ovulatory menses. During the first and fourth phases of the menstrual cycle (as determined by urinary luteinizing hormone peak and basal body temperature shift), subjects received tobramycin by intravenous bolus. Tobramycin half-life, total body clearance, and volume of distribution were not significantly different between the two study phases. No significant change in total urinary creatinine excretion or CL(CR) was seen between phases. Total 24 hour urinary recovery of tobramycin was 98-99.7%. We conclude that no significant changes in renal function, as evaluated by tobramycin pharmacokinetics and CL(CR), occur between these hormonally different phases of the menstrual cycle, and that urinary recovery of a single dose of tobramycin is nearly complete within 24 hours in premenopausal women with normal renal function.     

Effects of the menstrual cycle on timing and depth of breathing at rest

Volume and timing components of resting ventilation were measured serially in 40 women aged 18 to 36 yr, during menstrual, follicular and luteal phases of menstrual cycle. Resting minute ventilation (VE) was significantly higher (P < 0.001) in luteal phase than in menstrual and follicular phases; in the two latter phases VE was almost equal. This increment in VE during the luteal phase was due to a significant rise (P < 0.001) in tidal volume (VT). Respiratory frequency (f) was unchanged throughout the cycle. Although there was a mean increases in inspiratory time (T1) during the luteal phase compared to the other two phases, the difference did not reach statistical significance. Duty cycle, T1/Ttot, was also unchanged throughout menstrual cycle. However, mean inspiratory flow, VT/T1, was significantly higher (P < 0.05 and P < 0.01) during luteal phase as compared to that during menstrual or follicular phases respectively. Pulmonary mechanics, as measured by forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced mid expiratory flow rate (FEF25%, 75%), were within normal limits and remained unaltered during the menstrual cycle. Therefore, in the absence of alteration of pulmonary mechanics, the luteal increase in ventilation and inspiratory flow suggests a possible role for progesterone in stimulating the respiratory drive, either centrally or through the peripheral chemoreceptors or by both.     

Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle.

Preclinical and clinical studies suggest that females may be less vulnerable to cocaine's toxic effects than males. The pharmacokinetics of intravenous cocaine (0.2 and 0.4 mg/kg) were measured in 12 men and 22 women with a history of cocaine abuse, matched with respect to age and body mass index (BMI). Women were studied during the follicular and the luteal phases of the menstrual cycle. There were no differences between men and women in pharmacokinetic measures [peak plasma cocaine levels (Cmax), elimination half-life (T 1/2 min), area under the curve (AUC)] or cardiovascular or subjective effects "high" measures. Heart rate increases were cocaine dose-related (p < .01-.02) and also did not differ between men and women. Cocaine's pharmacokinetic and pharmacodynamic effects were similar in men and women, and in women during the follicular and mid-luteal phases of the menstrual cycle.     

The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women

RATIONALE: Few studies have systematically determined whether the response to cocaine in human females is related to hormonal fluctuations at different phases of the menstrual cycle. OBJECTIVES: To investigate the responses to repeated doses of smoked cocaine in women during two phases of the menstrual cycle using a within-subject design. METHODS: Eleven non-treatment seeking female cocaine smokers were administered smoked cocaine during the follicular and mid-luteal phases of the menstrual cycle. The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, there were four cocaine administration sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12, or 25 mg cocaine base, depending on the session) at 14-min intervals. RESULTS: The number of cocaine doses administered did not vary between the follicular and luteal phases. After cocaine administration, heart rate and several ratings - such as "good drug effect", "high", "stimulated", and "drug quality ratings" - were increased more during the follicular phase than the luteal phase, although, for some measures, these effects varied based on the cocaine dose. Further, dysphoric mood during the luteal phase was improved after cocaine administration. CONCLUSIONS: These results indicate that the cardiovascular and subjective effects of repeated doses of smoked cocaine are complex and vary as a function of menstrual cycle phase and cocaine dose.     

Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase

Background

In previous studies with male and female rhesus monkeys, withdrawal of access to oral phencyclidine (PCP) self-administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females, and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer impulsive choice for SACC increased during PCP withdrawal more in males than females.

Objectives

The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle.

Materials and methods

In component 1, PCP and water were available from two drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In component 2, a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or six delayed SACC deliveries, and the delay was increased by 1 s after a response on the delayed lever and decreased by 1 s after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP withdrawal, that occurred during the mid-follicular phase (days 7–11) or the late luteal phase (days 24–28) of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases.

Results

PCP deliveries were higher during the luteal (vs follicular) phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration.

Conclusions

PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys.     

Sex and menstrual cycle effects on progressive ratio measures of cocaine self-administration in cynomolgus monkeys.

Fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence the abuse-related effects of acute cocaine administration in women and chronic cocaine self-administration in rodents, but there have been no comparable studies in non-human primates. The interactions among sex, menstrual cycle phase, and cocaine self-administration (0.0032, 0.01, and 0.032 mg/kg/injection (inj)) under a progressive ratio schedule were investigated in four female and two male cynomolgus monkeys. Females were given unrestricted access to cocaine across 54 menstrual cycles, and males were studied over 23 pseudo-cycles of 30 days duration. Ovulatory cycles were defined by luteal phase elevations in progesterone and 44 cycles were ovulatory. During ovulatory menstrual cycles, females reached significantly higher progressive ratio break points than males at all three unit doses of cocaine (P<0.001). During anovulatory cycles, females also reached significantly higher break points than males for 0.032 mg/kg/inj cocaine (P<0.01). Progressive ratio break points for cocaine (0.01 and 0.032 mg/kg/inj) did not vary significantly as a function of ovarian steroid hormone levels during the follicular and the luteal phase of ovulatory menstrual cycles, or during anovulatory cycles. Progressive ratio break points for 0.0032 mg/kg/inj cocaine were significantly higher during the follicular phase than during the late luteal phase (P<0.05-0.001). There were no systematic changes in progressive ratio break points in male pseudo-cycles. Significant cocaine dose-related sex differences were observed, but no consistent changes in cocaine self-administration as a function of menstrual cycle phase, or levels of estradiol and progesterone, were detected in female cynomolgus monkeys.     

Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women

BACKGROUND AND OBJECTIVES: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP 1A2 activity is not clear. METHODS: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean +/- SD) 27.8 +/- 3.8 years, body mass index 23.8 +/- 3.8 kg x m-2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 +/- 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. RESULTS: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day -9 to -4 prior to onset of the next menses) to the follicular phase (days 5-10) was (n = 13, point estimate) 1.03 (90% CI 0.95-1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. CONCLUSIONS: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates.     

Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green.

1. The applicability of a continuous infusion of indocyanine green (ICG) to detect changes in apparent hepatic blood flow (HBF) was investigated in six healthy subjects. 2. High-performance liquid chromatography was used to measure ICG concentrations, and the effect of intravenous propranolol (10 mg in 10 min) on HBF was investigated. 3. During 150 min infusions of ICG (1.0 mg min-1) steady-state was reached within about 30 min and thereafter the plasma dye concentration remained essentially constant until the end of infusion. 4. Blood clearance (CLb) of ICG (15.9 +/- 2.2 ml min-1 kg-1; mean +/- s.d.), calculated as infusion rate/blood dye concentration over three time periods (30-50, 80-100 and 130-150 min) during the 150 min infusion, was not different from that obtained with three 1-min infusions (0.5 mg kg-1) administered at corresponding times of the day (CLb = 14.0 +/- 2.2 ml min-1 kg-1, P = 0.06). 5. The pharmacokinetics of ICG were shown to be linear up to plasma concentrations of at least 3 micrograms ml-1 using variable infusion rates (0.5, 1.0 and 2.0 mg min-1). 6. Propranolol had little effect on ICG concentrations during continuous infusion. The AUC of ICG from the start of propranolol infusion up to 125 min thereafter was increased by 12% +/- 17% (P = 0.21) compared with placebo.     

Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics

Objective: Pregnanolone is a 3α-hydroxylated-5β-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. Methods: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. Results: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml · min⁻¹ · kg⁻¹ and 64.0 ml · min⁻¹ · kg⁻¹, depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. Conclusion: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects. Received: 16 September 1998 / Accepted in revised form: 27 November 1998     

Influence of endogenous progesterone on alprazolam pharmacodynamics.

The results of a recently completed study demonstrated that postmenopausal women were more sensitive to triazolam-induced psychomotor performance impairment when progesterone was administered concomitantly. That clinical evidence agrees with the emerging in vitro information regarding the rapid membrane effects of a progesterone metabolite that positively modulates the gamma-aminobutyric acid-A-benzodiazepine receptor complex. The objective of this study in premenopausal women was to determine whether the response to a benzodiazepine is altered when endogenous progesterone concentrations are high (luteal phases of a menstrual cycle) compared with when progesterone concentrations are low (follicular phases of a menstrual cycle). The pharmacokinetics and pharmacodynamics of oral alprazolam were evaluated in twelve healthy, normally menstruating women who were not receiving oral contraceptive agents. On two separate occasions, once during each phase of the menstrual cycle, the women randomly received an oral alprazolam 2-mg dose. Blood samples were collected, and psychomotor performance tests were conducted at selected times before and after dosing. These data show that fluctuations of endogenous progesterone across the menstrual cycle do not influence alprazolam pharmacodynamics. Despite endogenous progesterone concentrations being significantly higher during the midluteal than during the midfollicular drug administrations, no differences were observed in either the digit-symbol substitution test, card sorting by suit, or sedation scores on these two occasions. No pharmacokinetic differences were observed between the two menstrual cycle-phase drug administrations. In conclusion, the lack of changes during the menstrual cycle in demonstrable cognitive impairment and pharmacokinetics after alprazolam administration is reassuring. This implies that a dose adjustment made on the basis of menstrual timing is not required.     

Effects of menstrual cycle phase on the reinforcing effects of phencyclidine (PCP) in rhesus monkeys

Substantive evidence indicates that there are sex differences in the reinforcing effects of drugs, and gonadal steroid hormones, such as estrogen and progesterone, likely contribute to these differences. Among females, subjective effects of drugs differ as a function of menstrual cycle phase. The purpose of the present study was to compare oral self-administration of phencyclidine (PCP) in female rhesus monkeys (Macaca mulatta) across different phases of the menstrual cycle. Since the 28-day menstrual cycle of non-human primates is similar to that of humans, this model could provide important evidence supporting the implication that changes in the levels of gonadal hormones across menstrual phase can alter a drug's reinforcing effects. Oral self-administration of several concentrations of PCP (0.125, 0.25, and 0.5 mg/ml) was examined in three sexually mature female monkeys during 3-h experimental sessions. Menstrual cycle phase was determined by onset of menses and verified by examining vaginal cytology. PCP self-administration was greater during the luteal phase at the 0.125 and 0.25 mg/ml concentrations, which is normally characterized by high levels of progesterone and moderate levels of estrogen, than during the follicular phase, when levels of estrogen are increasing and progesterone levels are low. When examined within each phase, numbers of PCP deliveries were highest during the mid-luteal phase, compared to the early and mid-follicular phases. No differences in self-administration were observed between early and mid-follicular phases, but a significant difference in PCP deliveries was found between mid- and late luteal phases at the lowest concentration of PCP tested. The results from this study suggest that PCP's reinforcing effects in female monkeys differ as a function of menstrual cycle phase.     

Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and females in either phase of the cycle. The elimination half-life was 27.3 +/- 1.3 h in males, 27.7 +/- 1.5 h in females in the follicular phase and 29.6 +/- 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 +/- 2.7 ml/min, 58.2 +/- 3.3 and 55.8 +/- 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 +/- 2.3 and 31.2 +/- 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 +/- 4.6 and 45.6 +/- 4.1 ml/min) was significantly lower than in males (P less than 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 +/- 0.1%) to females in the luteal phase of the cycle (12.4 +/- 0.5%) to females using OC-steroids (13.5 +/- 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (Cli = 323 +/- 30 ml/min in females using OC-steroids, 530 +/- 37 ml/min in males and 459 +/- 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have highly steady levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.     

Effects of gender and menstrual cycle phase on food-maintained responding under a progressive-ratio schedule in cynomolgus monkeys

Clinical and preclinical data suggest that fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence spontaneous feeding behavior in females. The effects of gender, menstrual cycle phase, and ovarian hormone fluctuations on food-maintained responding under a progressive-ratio schedule were investigated in four female and three male cynomolgus monkeys. Females were studied across 21 menstrual cycles, and ovulatory cycles were defined by analysis of ovarian steroid hormone levels. Data were analyzed for the early and mid-follicular phase and the mid- and late luteal phase of the menstrual cycle. Progressive-ratio break points for food were significantly higher in males than in females (p < 0.01). However, progressive-ratio break points did not vary consistently as a function of menstrual cycle phase during ovulatory cycles. There were no systematic patterns of progressive-ratio break points in anovulatory menstrual cycles. Only one female monkey reached significantly higher break points during the mid- and late luteal phases in comparison to the mid-follicular phase of the menstrual cycle (p < 0.05). There was also a significant positive correlation between progressive-ratio break points and progesterone levels and a significant negative correlation with estradiol in that monkey. Although fluctuations in ovarian steroid hormones may influence food consumption under some conditions, consistent patterns of food-maintained responding were not detected during ovulatory menstrual cycles in cynomolgus monkeys.