The influence of the menstrual cycle on triazolam and indocyanine green pharmacokinetics

The aim of this study was to investigate the effects of the menstrual cycle phase on the pharmacokinetics of two high-clearance agents, triazolam and indocyanine green (ICG). Eleven nonsmoking, healthy, eumenorrheic women were enrolled in this study. Triazolam (0.25 mg) was administered orally, and indocyanine green was administered as an i.v. bolus (0.5 mg/kg) during the follicular, ovulatory, and luteal phases of a single menstrual cycle. Blood samples were collected over 10 hours for triazolam and over 30 minutes for ICG. Triazolam and indocyanine green concentrations were quantitated by electron capture gas chromatography and spectrophotometry, respectively. Noncompartmental analysis was used to determine relevant pharmacokinetics parameters, which were statistically assessed using two-way ANOVA (p < 0.05). No statistical differences for triazolam were observed. Vd/F was lower in the luteal phase (107 L) as compared to the follicular (138 L) and ovulatory (133 L) phases. Clearance of triazolam was comparable in the follicular (583 ml/min), ovulatory (565 ml/min), and luteal (538 ml/min) phases. ICG also revealed no significant differences across the phases. These results suggest that the phases of the menstrual cycle do not influence triazolam or ICG pharmacokinetics.     

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.     

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.     

Pharmacokinetic changes of theophylline and amikacin through the menstrual cycle in healthy women

The objective of this open-label, single-dose study was to clarify the influence of the menstrual cycle on the pharmacokinetics of theophylline (n = 10) and amikacin (n = 8) in young healthy Japanese women with regular menstrual cycles. Each subject received an intravenous infusion of theophylline or amikacin sulfate at four different phases--mid-follicular (phase I), peri-ovulatory (phase II), mid-luteal (phase III), and premenstrual days (phase IV). In the theophylline study, there were no significant differences in the pharmacokinetic parameters among the four phases studied. In the amikacin study, CLtot was 15% higher in phase III than in phase I (p < 0.01). Vd beta was 35% higher in phase III than in phase I (p < 0.05). The other pharmacokinetic parameters of amikacin were not significantly altered during the menstrual cycle. Evidence suggests that the phase of the menstrual cycle may be a factor in determining the pharmacokinetics of amikacin.     

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.     

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.     

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.     

Influence of the menstrual cycle on theophylline pharmacokinetics in asthmatics

Summary The effect of menstrual cycle on the pharmacokinetics of theophylline has been studied in 9 female asthmatic patients. At three different times during the cycle (first, tenth and twentieth days) each subject received an i.v. infusion of 240 mg theophylline. Significant changes were found in the kinetics of theophylline according to the menstrual cycle. The maximum plasma drug concentration, minimum mean residence time, and minimum elimination half-life were observed at mid-cycle. The lowest clearance was observed at D 20. The AUC and volume of distribution did not vary significantly during the cycle.     

Salivary paracetamol elimination kinetics during the menstrual cycle.

Studies were done to examine the influence of the menstrual cycle on the elimination kinetics of paracetamol. Salivary concentrations of paracetamol were determined after oral administration of 1 g of paracetamol on day 3, 10, 14, 20 and 25 of the menstrual cycle in normal healthy women volunteers with regular menstrual cycles. There was no significant difference in elimination half-life (t 1/2) or metabolic clearance rate (CL) between the various days of the menstrual cycle. The result suggests that paracetamol kinetics are not altered by the hormonal changes occurring during the menstrual cycle.     

Effect of niprisan on single oral dose pharmacokinetics of paracetamol in rats.

The single oral dose pharmacokinetics of paracetamol was studied alone and after coadministration with NIPRISAN In rats. Paracetamol concentrations were measured in rat plasma using UV-spectrophotometer and the data were fitted into an open two-compartment pharmacokinetic model using the computer program (STATIS Version 3.0). Results indicated no significant difference in the absorption of paracetamol between study and control groups but a significant reduction (p < 0.05) at some sampling time as the dose of NIPRISAN was increased double-fold. The pharmacokinetic parameters showed only 1.51 and 7.19% reduction in AUC(0-infinity) and Cmax respectively for paracetamol (20 mg/kg) + NIPRISAN (500 mg/kg). It was thus concluded that the gastric presence of NIPRISAN did not significantly reduce the absorption of paracetamol in rats.     

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     

Influence of menstrual cycle on antipyrine pharmacokinetics in healthy Indian female volunteers.

The effect of the menstrual cycle on antipyrine pharmacokinetics was studied in 11 normal, healthy Indian female volunteers. Antipyrine half-life, apparent volume of distribution, clearance and AUC were calculated by standard methods. Results indicated that in females, antipyrine half-life was significantly longer on day 5 as compared with that on days 15 and 21 of the menstrual cycle. It appears that hormonal changes during the menstrual cycle affect the pharmacokinetics of drugs in normal healthy females.     

Comparison of the pharmacokinetics of paracetamol from two generic products in patients after total gastric resection

Gastrectomy leads to pathophysiological changes within the alimentary tract, which may affect drug absorption and pharmacokinetic parameters (PK). The need to apply orally administered analgesics in this group of patients is often related with alternative application of currently available generic products. Thus, from the clinical point of view it is necessary to evaluate the PK of these drugs to confirm their equivalence. The aim of the study was therefore an analysis of the pharmacokinetics of paracetamol from two generic products in patients after total gastric resection. The research was carried out on two groups of patients after gastrectomy with Roux-en-Y reconstruction (n = 30; mean [SD] age, 63.0 [11.5] years; weight, 67.6 [13.7] kg; and height, 166.4 [9.1] cm). The patients received paracetamol in a single orally administered dose of 1,000 mg. Blood samples were collected within 6 h of drug administration. The concentration of paracetamol and paracetamol glucuronide in the blood plasma was marked by means of a validated high-pressure liquid chromatography with ultraviolet detection (HPLC-UV). The main PK for paracetamol in group 1 (n = 17) and 2 (n = 13) were as follows: C(max), 9.46 (3.66) and 12.79 (5.32) μg/ml, respectively (p = 0.0517); AUMC(0-t), 77.64 (30.37) and 51.01 (15.76) μg h(2)/ml (p = 0.0046); AUC(0-inf), 41.61 (23.52) and 30.28 (9.74) μg h/ml (p = 0.0862); t(max), 1.68 (0.63) and 0.50 (0.25) h (p < 0001). The obtained C(max) and AUC values in patients after gastrectomy were reduced in comparison with healthy subjects. Total gastrectomy therefore affected the pharmacokinetics of paracetamol administered in tablets. In our patients, we also observed significant differences between the PK of paracetamol and two generic preparations. These two drugs can thus be used interchangeably, but with caution.     

Effect of study protocol on the interactions between cimetidine and paracetamol in man.

The influence of cimetidine (400 mg) on the salivary pharmacokinetics of oral paracetamol (1 g) was studied in 8 healthy subjects under two protocols--concomitant and delayed administration of cimetidine. There were no significant changes in the salivary pharmacokinetics of paracetamol when the two drugs were concomitantly administered (P > 0.100). Delayed administration of paracetamol 1 h after cimetidine, on the other hand, was associated with significant changes as compared to control. The peak salivary concentration (Cmax) and absorption rate constant (Kab) were significantly reduced (P < 0.05), while the time to peak concentration (Tmax), absorption half-life constant (t1/2ab) and lag time were all significantly increased (P < 0.05). Elimination half-life (t1/2el) was also significantly increased (P < 0.05). These findings indicated that cimetidine does not affect the pharmacokinetics of paracetamol when the two drugs were concomitantly administered but impaired the absorption of paracetamol when the administration of the latter was delayed by 1 h after cimetidine. The therapeutic implication of this interaction is that the efficacy of paracetamol may be affected.     

Paracetamol interaction with oral contraceptive steroids: increased plasma concentrations of ethinyloestradiol.

The effect of a single dose of paracetamol (1 g) on plasma concentrations of the oral contraceptive steroids ethinyloestradiol (EE2) and levonorgestrel (LNG) has been studied in six healthy female volunteers. The area under the plasma concentration-time curve (AUC0-24) of EE2 was significantly increased following paracetamol administration by 22% (control 2221 +/- 291; following paracetamol, 2702 +/- 452 pg ml-1 h; mean +/- s.d.; P less than or equal to 0.05). The greatest effect was evident in the time period 0-3 h. There was a significant decrease in the AUC of EE2-sulphate after paracetamol (7736 +/- 3791 pg ml-1 h) compared with control (13161 +/- 4535 pg ml-1 h; P less than or equal to 0.05). Plasma concentrations of LNG were unaltered by concurrent paracetamol administration. We conclude that the administration of a single 1 g dose of paracetamol causes an increase in plasma concentrations of EE2 as a result of a reduction in the sulphation of the steroid. This interaction may be of clinical significance in women on oral contraceptive steroids who regularly take paracetamol.     

Blood and Plasma Pharmacokinetics of Ciclosporin in Diabetic Kidney Transplant Recipients

BACKGROUND AND OBJECTIVES: Long-term diabetes mellitus may affect the absorption, distribution and metabolism of immunosuppressive agents used after organ transplantation. The aims of this study were to characterize ciclosporin pharmacokinetics in blood and plasma and to compare the ciclosporin unbound concentration and the blood : plasma concentration (B : P) ratio in diabetic kidney transplant recipients. PATIENTS AND METHODS: Ciclosporin 12-hour steady-state pharmacokinetics were studied in eight diabetic and nine nondiabetic patients. Ciclosporin concentrations in whole blood and in plasma were measured using liquid chromatography-tandem mass spectrometry, and the ciclosporin fraction unbound (f(u)) was determined by an equilibrium dialysis method utilizing [(3)H]ciclosporin as a tracer. Oral absorption of paracetamol (acetaminophen) was used as a marker for gastric emptying. RESULTS: In diabetic patients, the time to the peak blood ciclosporin concentration at steady state (t(max)(,ss)) was prolonged (128 minutes vs 93 minutes in nondiabetic patients, p < 0.01) and, on average, the paracetamol t(max) was prolonged by 30 minutes. The whole-blood dose-normalized area under the concentration-time curve from 0 to 12 hours (AUC(12)) was marginally lower in diabetic patients (p = 0.09) and the plasma AUC(12) was significantly lower (p = 0.03). The ciclosporin f(u) was numerically higher in diabetic patients (1.20 +/- 0.65% vs 0.72 +/- 0.28% in nondiabetic patients, p = 0.066); however, the unbound concentration values were essentially similar in the two groups (0.58 +/- 0.76 microg/L in diabetic patients and 0.52 +/- 0.48 microg/L in nondiabetic patients; p = 0.59). No difference was observed in the ciclosporin B : P ratio between the two groups. CONCLUSION: This study indicates that diabetes delays ciclosporin absorption, reduces ciclosporin exposure and increases the ciclosporin f(u) but not the pharmacologically active unbound concentration.     

Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender.

Sustained-release (SR) bupropion (Zyban) is approved as a smoking cessation aid for adults. Since smoking often begins in adolescence, we determined the single-dose pharmacokinetics of bupropion SR in 75 adolescent subjects ranging from 13 to 18 years old. Subjects self-reported their smoking status. Urinary cotinine concentration was used to verify smoking status. Thirty-seven subjects (18 males, 19 females) were classified as cigarette smokers and 38 were nonsmokers (19 males, 19 females). Fasted subjects received one tablet (150 mg) of bupropion SR, and plasma samples were collected before (0) and 1/2, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for bupropion and its three major metabolites (hydroxybupropion and the aminoalcohol isomers, erythrohydrobupropion plus threohydrobupropion, expressed as a composite) by solid-phase extraction, followed by LC/MS/MS. Factorial analysis of variance (ANOVA) was used to evaluate the effects of smoking and gender on pharmacokinetic parameters. Smokers and nonsmokers differed significantly (p < 0.05) in age and urinary cotinine (p < 0.01) concentration but did not differ significantly in mean weight, height, body surface area, or body mass index. The pharmacokinetic (PK) parameters for bupropion and hydroxybupropion did not differ between smokers and nonsmokers, but differences were found between male and female subjects. Mean values for area under the plasma concentration versus time curve (AUC0-->infinity), volume of distribution (Vd beta) normalized to body weight, maximum plasma concentration (Cmax), and elimination half-life (t1/2 beta) for bupropion were significantly (p < 0.05) greater in females than males, while clearance of bupropion normalized to body weight (CL/f) did not differ between males and females. Females also exhibited significantly (p < 0.05) larger values for hydroxybupropion mean AUC0-->infinity and Cmax than males. The mean ratio of hydroxybupropion to bupropion AUC for adolescents was approximately 4 to 5, which is lower than that previously reported for adults. In conclusion, smoking status does not affect the single-dose pharmacokinetics of bupropion SR in adolescents. However, females differ from males in several potentially important PK parameters for bupropion and its major metabolite, hydroxybupropion.     

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.     

Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine.

The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.     

Steady state relative bioavailability and pharmacokinetics of oral propranolol in black and white North Americans

The steady state bioavailability and pharmacokinetics of propranolol over two consecutive dosing intervals were investigated in 18 black and 10 white normal volunteers following the administration of 20 mg of a test and reference oral dosage form, respectively, every 6 h. There were no differences (p greater than 0.05) between dosage forms in the mean (n = 28) area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) or time to Cmax (tmax) for propranolol or its active metabolite, 4-hydroxypropranolol. However, as a group blacks had lower plasma concentrations of propranolol during the second dosing interval (AUC-2 and Cmax-2, respectively) were significantly (p less than 0.05) lower in blacks, but there were no ethnic differences (p greater than 0.05) in tmax. The mean AUC and Cmax for the 4-hydroxylated metabolite during both dosing intervals were significantly (p less than 0.05) lower in blacks. Mean oral clearances of propranolol, assuming complete absorption, (range: 42.1-54.5 ml min-1 kg-1) were similar (p greater than 0.05) in each racial group. There were no substantial changes in heart rate or blood pressure in blacks or whites following propranolol administration. These data suggest that for oral propranolol, blacks have different absorption and disposition characteristics than whites.