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.     

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.     

Timing and magnitude of changes in basal energy expenditure during pregnancy in Indian women

Basal energy expenditure (BEE) was determined in 291 pregnant women, age 20-35 years, using Benedict Roth Metabolism Apparatus. A control study was undertaken in 38 non pregnant women during both follicular and luteal phases of menstrual cycle respectively. The mean +/- SD of BEE were found to be 34.04 +/- 3.05, 35.85 +/- 2.60 and 39.69 +/- 2.75 Kcal/m2/hr during first, second and third trimesters of pregnancy respectively. BEE was progressively and significantly increased (P < 0.01). However, increase in BEE during first trimester of pregnancy compared to that of luteal phase of menstrual cycle was insignificant. The results indicate that Indian pregnant women should maintain energy requirements by increasing caloric intake throughout the gestation.     

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.     

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.     

PLASMA NORADRENALINE AND ITS RELATIONSHIP TO PLASMA OESTRADIOL IN NORMAL WOMEN DURING THE MENSTRUAL CYCLE

In order to investigate a possible relationship between sympatho-adrenal neuronal activity and the endocrine changes during the menstrual cycle, free and sulphate-conjugated plasma catecholamines and oestradiol were measured under carefully controlled conditions in 26 normal menstruating women. Plasma oestradiol levels were generally higher during the luteal compared with the follicular phase which corresponded to the self-reported day of the cycle. Free plasma noradrenaline concentration was higher during the luteal phase (P = 0.02) and was positively correlated with plasma oestradiol concentration (r = 0.40, P = 0.023). These relationships were not present for plasma adrenaline. It is conceivable that the higher luteal phase noradrenaline is causally related to the higher oestradiol levels, leading to incomplete inactivation by reducing tissue uptake or competitive inhibition of catechol-O-methyl transferase. As sulphated noradrenaline was not significantly different between the follicular and luteal phases, competitive inhibition of phenolsulphotransferase by oestradiol was considered unlikely.     

Levels of urinary human chorionic gonadotrophin (hCG) following conception and variability of menstrual cycle length in a cohort of women attempting to conceive

ABSTRACT

Objectives: To define the variability of menstrual cycle length and contribution of follicular and luteal phases to overall cycle variability, and to examine the rise in urinary hCG in early pregnancy.

Methods: Menstrual cycle study. Urine samples from 101 women (recruited from two south-east counties in the UK) were assayed to determine day of luteinising hormone (LH) surge, lengths of follicular and luteal phases and correlations with total menstrual cycle length. HCG study. Daily urine samples collected from 86 women prior to conception until 43 days post-conception were assayed for hCG and examined versus time since LH surge, determined using fertility test kits.

Results: Mean menstrual cycle length was 27.7?±?3.4 days, mean follicular phase length was 14.5?±?3.4 days and mean luteal phase length was 13.2?±?1.9 days. Total cycle lengths varied between and within women. There was a significant correlation (r²?=?0.70) between follicular phase length and total cycle length; luteal phase length was less variable and showed no association with total cycle length. Concentrations of hCG were significantly similar between women when referenced against the day since LH surge. Three thresholds were determined to indicate time since conception as 1–2 weeks, 2–3 weeks and 3+ weeks.

Conclusions: Total cycle length variation is mainly determined by follicular phase variation and predicting menses onset to estimate time of pregnancy testing is unreliable. Evaluating concentrations of hCG relative to LH surge results in consistent increases between women up to 21 days after conception. Therefore, urinary hCG concentration can be used to accurately estimate time since conception.     

Luteal-phase accentuation of acoustic startle response in women with premenstrual dysphoric disorder.

Alterations in central nervous system response to menstrual cycle-related fluctuations in neuroactive steroids are thought to underlie the emergence of negative affect in the luteal phase of the menstrual cycle in women with premenstrual dysphoric disorder (PMDD). Such changes in the neuroendocrine milieu may lead to heightened arousal and response to stress in women with PMDD. Using the acoustic startle paradigm, we sought to determine whether women with PMDD have an accentuated physiologic response to a mildly aversive stimulus during the luteal compared to follicular phase. Further, we also examined the impact of visual affective stimuli on acoustic startle response (ASR) magnitude. During the follicular and luteal phases of the menstrual cycle, acoustic stimuli (103 dB) were delivered to 15 women with PMDD and 14 healthy menstruating women of similar age. After obtaining baseline ASR, the procedure was repeated when subjects viewed pleasant, neutral and unpleasant pictures. There was a significant group by menstrual cycle phase interaction for baseline ASR magnitude, which can be attributed to the heightened startle magnitude in women with PMDD compared to healthy women during the luteal relative to the follicular phase. The direction and degree to which picture viewing modulated the startle magnitude did not vary by group or menstrual cycle phase. These data suggest that menstrual cycle phase has a powerful modulatory effect on physiologic reactivity in women with PMDD but not in healthy women. Physiologic response to affective stimuli appears to be intact in women with PMDD across 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.     

Response to alcohol in women: role of the menstrual cycle and a family history of alcoholism

The present study determined whether: (1) the response to alcohol varied as a function of menstrual cycle phase and (2) women with a paternal history of alcoholism (FHP) were less sensitive to the effects of alcohol compared to women without a family history of alcoholism (FHN). The behavioral effects of alcohol (0.00, 0.25, and 0.75 g/kg) were evaluated in 21 FHN and 24 FHP women; each dose was tested during both the midfollicular and late luteal phases of the menstrual cycle. Baseline negative mood was increased during the luteal phase compared to the follicular phase (increased Beck Depression scores and decreased Vigor, Arousal, and Friendly scores). Alcohol increased ratings of Drug Liking and Good Drug Effect more in the luteal phase than the follicular phase. FHP women had greater negative mood during the luteal phase and some of these dysphoric effects were increased by alcohol more in FHP women than FHN women. Alcohol impaired performance, with no group or menstrual cycle differences. However, consistent with previous studies, FHP women were less impaired by alcohol than FHN women on the balance task. These data indicate that (1) the differences in response to alcohol across the menstrual cycle are subtle, although alcohol is liked more during the luteal phase; (2) increases in dysphoric mood during the luteal phase are more pronounced in FHP women compared to FHN women, particularly after alcohol; and (3) the differences observed in response to alcohol between FHP and FHN women are less pronounced than previously shown in men.     

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.     

Adolescent nicotine exposure sensitizes cue-induced reinstatement of cocaine seeking in rats bred for high and low saccharin intake

Background

Quit attempts may have different outcomes based on menstrual cycle phase on quit day. This is the first preliminary study examining whether smoking cessation outcomes vary by menstrual cycle phase of quit date in women receiving a 6-week open trial of sustained release (SR) bupropion.

Methods

Thirty-three treatment-seeking premenopausal women were studied. Abstinence outcomes were compared for women quitting during the luteal versus follicular phase.

Results

Women receiving bupropion SR whose self-selected quit date occurred in the luteal phase had significantly higher rates of point prevalence abstinence during the final week of a 6-week post-quit treatment period than women quitting in the follicular phase (62.5% versus 29.4%; p < 0.05). A similar, but non-significant, pattern of findings was demonstrated for continuous abstinence during the treatment phase and for point prevalence abstinence at 3-month follow-up.

Conclusions

Women receiving bupropion SR were significantly more likely to be abstinent at treatment completion if quitting occurred during the luteal phase. This is consistent with recent findings of outcome related to cycle phase at quit date in the absence of pharmacotherapy, and differs from findings utilizing nicotine replacement. Results add to emerging data suggesting that smoking cessation interventions with varying mechanisms of action may result in different outcomes for premenopausal women based on gonadal hormones at quit date.     

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.     

Menstrual cycle effects on caffeine elimination in the human female

Summary Increases in the levels of sex steroids due to pregnancy or oral contraceptive steroid use are known to decrease significantly the rate at which caffeine is eliminated from the body. An investigation has now been made into whether the changes in sex steroid levels that occur during normal menstrual cycling also affect the rate of caffeine elimination, especially whether hormonal shifts in the luteal phase are associated with slower elimination of caffeine. Repeated 24-hour caffeine elimination studies were conducted during the follicular and luteal phases of the menstrual cycle in 10 healthy women.Comparisons of the follicular and luteal phases revealed that systemic clearance of caffeine was slower in the luteal phase, although the t1,2 did not differ. The slowing effect was related to the proximity to onset of menstruation and to levels of progesterone.The evidence suggests that caffeine elimination may be slowed in the late luteal phase, prior to the onset of menstruation. Such a reduction would lead to increased accumulation of caffeine with repeated self-administration during the day, but the effect may be too small to be of clinical significance in the majority of women.     

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.     

The influence of menstrual cycle phase on sensitivity to ethanol-like discriminative stimulus effects of GABA(A)-positive modulators.

Previous studies showed that sensitivity to the ethanol-like discriminative stimulus effects of allopregnanolone and ethanol are enhanced during the luteal phase of the menstrual cycle when progesterone levels peak in monkeys trained to discriminate 1.0 g/kg ethanol. The present study further explored the influence of the menstrual cycle phase on the discriminative stimulus effects of ethanol, allopregnanolone, and midazolam. Female adult cynomolgus monkeys (Macaca fascicularis) were trained to discriminate 1.0 g/kg ethanol (n = 3) or 2.0 g/kg ethanol (n = 4) (20% w/v; i.g.) from water (i.g.). A cumulative dosing procedure was used to test discriminative stimulus effects of ethanol (0.5-2.5 g/kg; i.g.) and the ethanol-like discriminative stimulus effects of allopregnanolone (0.1-1.0 mg/kg; i.v.) or midazolam (1.0-17 mg/kg; i.g.) during the follicular vs. luteal phase of the menstrual cycle. In the 2.0-g/kg group, sensitivity to the ethanol-like effects of allopregnanolone was increased during the luteal vs. follicular phase in two of three monkeys. In contrast, average sensitivity to ethanol was not different in the luteal compared to the follicular phase in the 2.0-g/kg group. Finally, there was no difference in sensitivity to midazolam between the follicular and luteal phases in monkeys trained with either 2.0 g/kg or 1.0 g/kg ethanol. Overall, the ethanol-like discriminative stimulus effects of midazolam are not sensitive to the menstrual cycle phase. In addition, there was less influence of the menstrual cycle phase on allopregnanolone and ethanol sensitivity in a 2.0-g/kg compared to a 1.0-g/kg ethanol training dose.     

Subjective,Physiological, and Cognitive Responses to Intravenous Nicotine: Effects of Sex and Menstrual Cycle Phase

Nicotine dependence is a serious public health concern. Optimal treatment of nicotine dependence will require greater understanding of the mechanisms that contribute to the maintenance of smoking behaviors. A growing literature indicates sex and menstrual phase differences in responses to nicotine. The aim of this study was to assess sex and menstrual phase influences on a broad range of measures of nicotine response including subjective drug effects, cognition, physiological responses, and symptoms of withdrawal, craving, and affect. Using a well-established intravenous nicotine paradigm and biochemical confirmation of overnight abstinence and menstrual cycle phase, analyses were performed to compare sex (age 18–50 years; 115 male and 45 female) and menstrual cycle phase (29 follicular and 16 luteal) effects. Females had diminished subjective drug effects of, but greater physiological responses to, nicotine administration. Luteal-phase females showed diminished subjective drug effects and better cognition relative to follicular-phase women. These findings offer candidate mechanisms through which the luteal phase, wherein progesterone is dominant relative to estradiol, may be protective against vulnerability to smoking.     

Salt preference across different phases of menstrual cycle

It is well established that women experience food craving for particular foods and gain weight in relation to phases of menstrual cycle. In this study, the preference for different concentrations of salt sprayed on bland popcorn was assessed in 55 healthy women (age 18 to 22 yrs). Salt solutions of 0, 1, 2, 3 and +3 molar strength were used. Samples of sprayed popcorn were consumed in random order and preference marked on a Likert scale. It was observed that women preferred unsalted popcorn in the menstrual phase more than in the luteal phase. The preference for salted popcorn was most during the luteal phase and was proportionate to the strength of the salt solution used. Statistical analysis revealed significant differences in the preference rating between the menstrual phase and the other two phases. There was no significant difference in preference between the luteal and follicular phases.     

Evidence for a Role of Progesterone in Menstrual Cycle-Related Variability in Prepulse Inhibition in Healthy Young Women

Prepulse inhibition (PPI) of the startle response is sensitive to sex, with healthy young women showing less PPI compared with age-matched men, and varies according to the menstrual cycle phase in women. Relatively less is known regarding sex and hormonal influences in prepulse facilitation (PPF). Menstrual phase-related variability in PPI is suggested to be mediated by fluctuating estrogen level, based on the observations of more PPI in women during the follicular, relative to the luteal, phase. No study has directly assessed the relationship between fluctuating hormones and PPI or PPF levels over the human ovarian cycle. To examine the roles of circulating ovarian hormones in PPI and PPF, 16 non-smoking regularly menstruating healthy women were tested during both the follicular and luteal phases on PPI and PPF and provided saliva samples for measurement of 17β-estradiol (estrogen), progesterone and testosterone. The results showed higher levels of 17β-estradiol and progesterone during the luteal, relative to the follicular, phase; and more PPI during the follicular phase and more PPF during the luteal phase with comparable startle amplitude and habituation during the two phases. A larger increase in progesterone was associated with a smaller decrease in PPI from the follicular to the luteal phase. No significant associations were found between changes in PPI/PPF and estrogen levels. The findings confirm lower PPI during the luteal, compared with the follicular, phase and suggest a role for progesterone, more specifically an antipsychotic-like PPI-restoration action of progesterone, during the luteal phase in PPI of young women.     

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.