Age and gender influence the stereoselective pharmacokinetics of propranolol.

The effect of age and gender on the stereoselective pharmacokinetics of propranolol was studied in 12 young (25 to 33 years old) and 12 elderly (62 to 79 years old) healthy nonsmoking volunteers, half of whom were female. Racemic propranolol was administered (80 mg p.o.) each 8 hr for seven doses. Serum was obtained just before (0 time) and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after the final dose and analyzed for propranolol enantiomers. The serum concentration of alpha-1 acid glycoprotein was determined before propranolol administration. The binding of each enantiomer to serum proteins was determined in samples obtained before propranolol administration and two hr after the final dose of propranolol. We found that the intrinsic hepatic clearance of S-propranolol was about 30% smaller in the elderly than in the young, whether it was calculated for total or unbound drug. Additionally, the elimination half-lives of both enantiomers were 2- to 3-fold prolonged in the elderly compared with the young. In all subjects regardless of age or sex the intrinsic hepatic clearance of the total (bound plus free) S-isomer was smaller than that of the R-isomer. There was no age-related difference in alpha-1 acid glycoprotein concentration or protein binding of either enantiomer of propranolol. However, there was a gender-related difference with the females having significantly greater binding of the S-enantiomer than the males.(ABSTRACT TRUNCATED AT 250 WORDS)     

15O]water pharmacokinetics: influence of age and gender in normal subjects.

PURPOSE: To compile a normal database for the characterization of global [15O]water pharmacokinetic behavior. PROCEDURES: The influences of age, gender, and body habitus on the pharmacokinetics of [15O]water were investigated in a series of normal subjects, N = 100 (50 males, 50 females, age = 19-79) who were participants in cognitive activation studies. Arterial blood was analyzed by autosampler and parametric images were constructed using a 40-second summed image and the autoradiographic model. RESULTS: Males and females were comparable with respect to age, number of injections administered, and dose (mCi) administered per injection but differed significantly with respect to height, weight, and normalized dose (mCi/kg). There were significant gender-based differences in the bolus arrival time, global cerebral blood flow (gCBF), area-under-the-curve (AUC), summed image concentration, and dose-normalized concentration but not dose-normalized AUC. Bolus arrival time, gCBF and dose-normalized AUC were significantly influenced by age. CONCLUSION: Age and gender are significant determinants of [15O]water pharmacokinetic behavior.     

Effects of age and gender on pharmacokinetics of cefepime.

The effects of age and gender on the pharmacokinetics of cefepime were examined in 48 volunteers following administration of a single 1,000-mg intravenous dose. Male and female subjects were divided into four groups, each consisting of 12 subjects, according to their age and gender. The young subjects were between 20 and 40 years of age and elderly subjects were between 65 and 81 years of age. Serial blood and urine samples were collected from each subject and were analyzed for cefepime by validated high-pressure liquid chromatographic assays with UV detection. Key pharmacokinetic parameters were calculated by noncompartmental methods. There were no gender-related differences in elimination half-life (t1/2) and weight-normalized total body clearance (CLT), renal clearance (CLR), and steady-state volume of distribution (Vss). Statistically significant age-related effects were found for t1/2, CLT, CLR, and Vss parameters. In different study groups, Vss ranged from 0.21 to 0.24 liter/kg. The values for Vss were significant greater for elderly subjects than they were for young subjects. The cefepime t1/2 was significantly longer in elderly subjects (about 3 h) than that observed in young subjects (about 2.2 h). The mean values for CLT and CLR in the four study groups ranged from 1.11 to 1.56 and 0.99 to 1.44 ml/min/kg, respectively. In elderly subjects, the estimates for CLT and CLR were significantly lower than those observed in young subjects. Linear regression revealed good correlations between clearance values of cefepime and creatinine. The magnitude of age-related changes in the pharmacokinetics of cefepime is not significant enough to recommend dosage adjustment in elderly patients with kidney functions normal for their age.     

The influence of age on the pharmacokinetics of the antiepileptic agent oxcarbazepine

The disposition of oxcarbazepine was studied in 12 young and 12 elderly healthy male and 12 young and 12 elderly healthy female volunteers, with emphasis on the influence of age. Oxcarbazepine was administered as a single dose of either 300 mg (men) or 600 mg (women), followed by multiple-dose (300 mg) administration twice a day for 7 days (men) or 6 days (women). Semilogarithmic plasma concentration-time curves showed an increasing decline at decreasing concentrations. Accumulation of the pharmacologically active metabolite monohydroxycarbamazepine was found to be more than one would anticipate on the basis of linear and unchanged pharmacokinetics. Saturation did not seem to occur at the level of renal excretion. No apparent differences between male and female volunteers were observed. A significant higher maximum concentration, higher area under the curve parameters, and a lower elimination rate constant were observed in the elderly. These observations are in line with a smaller renal clearance of monohydroxycarbamazepine in the elderly group. In a clinical situation, these age-related differences are not likely to have important implications. In general, treatment with oxcarbazepine was well tolerated.     

Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans

The effects of grapefruit juice (150 ml at -15, -10, -1/4, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo-controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)- and (R)-nitrendipine. There were highly significant differences in the area under the concentration-time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half-lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.     

Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol

Pharmacokinetics of the benzodiazepine bromazepam were evaluated in volunteer subjects who received single 6 mg oral doses followed by blood sampling during the next 48 hours. Age and gender effects were studied in 32 subjects, divided into young (aged 21 to 29 years) and elderly (aged 60 to 81 years) groups. Compared with young subjects, the elderly had significantly higher peak serum bromazepam concentrations (132 vs. 82 ng/ml), smaller volume of distribution (0.88 vs. 1.44 L/kg), lower oral clearance (0.41 vs. 0.76 ml/min/kg), and increased serum free fraction (34.8% vs. 28.8% unbound). However, gender had no significant influence on bromazepam kinetics. In 11 young female users of oral contraceptive steroids, compared with seven age- and weight-matched control women not using oral contraceptives, no differences in bromazepam kinetics were observed. Coadministration of cimetidine (1.2 gm daily) significantly reduced bromazepam clearance (0.41 vs. 0.82 ml/min/kg) and prolonged elimination half-life (29 vs. 23 hours). Propranolol (160 mg daily) significantly prolonged bromazepam half-life (28 vs. 23 hours), but the reduction in clearance associated with propranolol (0.65 vs. 0.82 ml/min/kg) did not reach significance. Bromazepam has the pharmacokinetic characteristics of benzodiazepines with half-life values between 20 and 30 hours. Consistent with its biotransformation pathway by hepatic microsomal oxidation, bromazepam clearance is significantly impaired in elderly individuals, by coadministration of cimetidine and possibly propranolol.     

The influence of dosage time of midazolam on its pharmacokinetics and effects in humans.

The influence of dosage time of midazolam on its pharmacokinetics and effects on the central nervous system were investigated in six healthy volunteers, with pharmacokinetic-pharmacodynamic modeling. Each volunteer received single oral doses of 15 mg midazolam on four separate occasions: 8 AM, 2 PM, 8 PM, and 2 AM. An almost significant circadian variation was found in elimination half-life, shortest at 2 PM (1.26 +/- 0.47 hours, mean +/- SD) and longest at 2 AM (1.57 +/- 0.44 hours) (p = 0.05). Drug effects measured were alpha activity of the electroencepalograph and P100 latency of the visual-evoked response. The maximum drug effect (Emax) model described the concentration-effect relationship, extended with either a threshold drug concentration or a sigmoidicity parameter. A significant circadian variation was found in baseline alpha activity: highest at 8 AM (109% +/- 19% of the 24-hour mean) and lowest at 2 AM (80% +/- 12%). For alpha activity the drug concentration at half-maximum effect of both threshold Emax model and sigmoid Emax model showed lower values at 8 AM and 2 AM and higher values at 2 PM and 8 PM. However, these differences were either not significant (p = 0.10, threshold model) or on the verge of statistical significance (p = 0.05, sigmoid model). No circadian variation was found in the parameters describing the effect on the visual-evoked response. We conclude that the sensitivity of the central nervous system to midazolam, as reflected in alpha activity, possibly shows a circadian variation.     

Difloxacin metabolism and pharmacokinetics in humans after single oral doses

By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.     

The pharmacokinetics of fluconazole in healthy Chinese adult volunteers: influence of ethnicity and gender

Objective: The purpose of the present study was to investigate and compare the influence of ethnicity (including Han, Mongolian, Korean, Hui and Uygur) and gender on the pharmacokinetics of fluconazole in healthy adult volunteers after administration of 200‐mg fluconazole tablet. Methods: Ten healthy subjects (five males and five females) of each ethnicity were recruited and given a single 200‐mg dose of fluconazole in tablet form. Blood samples were obtained before dosing and at various predetermined time points after administration up to 96 h. Drug levels were measured by high‐performance liquid chromatography. The blood concentration–time profiles were analyzed using a non‐compartmental approach to estimate the absorption parameters (AUC_(0–96), C_max and t_max), the distribution parameter (V_d) and the disposition parameters (t_1/2 and CL). Results: Ethnicity did not affect the parameter estimates, but gender did. However, the gender differences in pharmacokinetic parameter could be accounted for by differences in weight. There was a high linear correlation between weight and ln C_max, ln AUC (ln means natural logarithmic transformation), V_d and CL. Conclusions: Ethnicity (Chinese Han, Mongolian, Korean, Hui and Uygur) influences the pharmacokinetics of fluconazole tablet. However, there were statistically significant gender differences in AUC, C_max, V_d and CL. But these could be accounted for by weight differences. If fluconazole dose‐adjustment is deemed necessary, this can be done on a weight basis rather than gender basis.     

The pharmacokinetics of ceftibuten in humans

The pharmacokinetics of ceftibuten, a new oral cephalosporin, has been studied in humans. Ceftibuten is very well absorbed in young and old patients. Absorption may be slightly decreased by food or relatively high doses (800 mg). The pharmacokinetics have been well characterized in rising single-dose and multiple-dose studies. The half-life is relatively long for this class of drugs, being approximately 2-3 hr. Apparent plasma clearance (CL/F), is approximately 40-75 ml/min, and the renal clearance is approximately 30-50 ml/min, corresponding to the fraction excreted unchanged in the urine of approximately 60%-70% of the dose. The apparent volume of distribution after oral dosing (Vd/F) was approximately 0.2 L/kg. The half-life, plasma clearance, renal clearance, and fraction excreted in urine are not affected by increasing dose and are constant during multiple dosing. There is little drug accumulation during multiple dosing. Drug elimination is decreased in patients with renal insufficiency and dosing in these patients should be adjusted relative to creatinine clearance values. The drug penetrates very well to experimentally induced inflammatory fluid but produces negligible levels in breast milk. The drug has no effect on the pharmacokinetics of theophylline. The drug is well tolerated and has pharmacokinetic properties that are clinically advantageous.     

Effects of age, gender, and race/ethnicity on the pharmacokinetics of posaconazole in healthy volunteers

Posaconazole is a triazole antifungal for prophylaxis of invasive fungal infection and treatment of oropharyngeal candidiasis. We evaluated the effects of gender, age, and race/ethnicity (black or white) on the steady-state pharmacokinetics of posaconazole in two studies on healthy adult subjects (>or=18 years of age). Additionally, we explored the effect of P-glycoprotein expression and MDR1 genotype on posaconazole pharmacokinetics in black and white subjects. Age, gender, and race/ethnicity had no clinically relevant effects on posaconazole pharmacokinetics. No association was observed between any MDR1 single-nucleotide polymorphism and the area under the concentration-time curve for posaconazole. Posaconazole was safe and well tolerated regardless of age, gender, or race/ethnicity. In conclusion, age, gender, and race/ethnicity have no clinically relevant effects on the steady-state pharmacokinetics of posaconazole in healthy adults; therefore, dosage adjustments based on these covariates are unnecessary.     

The influence of weightlessness on pharmacokinetics

The primary hostile factor during a spaceflight is the lack of gravity, which can induce space motion sickness and act on bones, muscles and the cardiovascular system. These physiological effects may modify the pharmacokinetics of the drugs administered during the flight producing reduced pharmacological activity or appearance of adverse effects. Given the small number of spaceflights and the difficulties of conducting experiments during missions, pharmacokinetic data obtained in flight are insufficient to determine if drug monitoring is necessary for the drugs present in the onboard medical kit. Therefore, validated earthbound models like tail-suspension performed with animals and long-term bedrest performed with human volunteers are used to simulate weightlessness and to study the pharmacokinetic variations of either absorption, distribution, or elimination of drugs. As a result of these studies, it is possible to make some dosing recommendations but more information is necessary to predict with precision all of the pharmacokinetic variations occurring in spaceflight. To collect more pharmacokinetic information, head-down bedrest studies are still the best solution and as saliva is an appropriate substitution for plasma for some drugs, salivary sampling can be planned during flights.     

The effect of age on ranitidine pharmacokinetics

Oral ranitidine was given to 68 healthy subjects between 18 and 75 years old at a dosage of 150 mg twice a day for seven doses. Fifteen subjects were 18 to 35 years old (group I), 19 subjects were 36 to 50 years old (group II), 19 subjects were 51 to 65 years old (group III), and 15 subjects were 66 to 75 years old (group IV). Venous blood samples were drawn and the AUC from 0 to 12 hours, the maximum plasma concentration, the time of the maximum plasma concentration, the minimum plasma concentration, and the elimination t1/2 were determined. When groups III and IV were compared with groups I or II, significant (P less than 0.05) increases were seen in the AUC(0-12) (42% and 50%), the maximum plasma concentration (36% and 41%), the minimum plasma concentration (91% and 85%), and the elimination t1/2 (29% and 33%). Positive linear correlations were found when the AUC(0-12) (r = 0.68; P less than 0.01), the maximum plasma concentration (r = 0.34; P less than 0.01), the minimum plasma concentration (r = 0.55; P less than 0.01), and the elimination t1/2 (r = 0.46; P less than 0.01) were regressed with age. Our results suggest that it may be appropriate to consider dosage adjustments for patients over 50 years of age who take ranitidine.     

The influence of age and gender of an exercise model on self-efficacy and quality of therapeutic exercise performance in the elderly

This study examined whether self-efficacy and quality of exercise performance in healthy elderly adults was influenced by the age and gender of the model who demonstrated the exercises to them. Twenty men and 20 women over 60 years of age were randomly assigned to one of four groups who viewed a videotape of a model of similar or different age and gender. The participants imitated three different exercises performed by the model. Participants rated their self-efficacy for performing the exercises before observing the model and again after imitation with the model. Analysis of variance revealed that the gender of the model influenced self-efficacy ratings of women but not men (p = .041). Elderly women who observed young or old male models provided significantly lower ratings of self-efficacy (p < .05) about correctly performing the exercises than did elderly women who observed female models of either age category. Gender and age of the model did not influence self-efficacy ratings of elderly men. Two raters blinded to group membership rated the quality of the participants' exercise form. When participants performed the exercises following modeling, analysis of variance revealed that the gender of the model previously viewed did not affect form ratings. It was concluded that matching the gender of model and observer when the observer is an elderly woman may support the observer's belief that she can perform the exercises well. In turn, this may benefit adherence to an exercise program.     

The pharmacokinetics of the antidepressant tianeptine and its main metabolite in healthy humans – influence of alcohol co-administration

A balanced 3 way cross-over study involving 12 young healthy volunteers (6 men and 6 women) was used to determine the pharmacokinetic parameters of the antidepressant tianeptine following a single dose administered by oral and intravenous route. The influence of alcohol on the pharmacokinetics of tianeptine when given per os was also investigated. Kinetic parameters of metabolite MC5, the C5 side chain beta-oxidation product of tianeptine, were simultaneously determined. Following intravenous administration total clearance and volume of distribution of tianeptine were 230 +/- 59 ml.min-1 and 0.47 +/- 0.14 l.kg-1 respectively. When given orally, tianeptine was absorbed rapidly (tmax = 0.94 +/- 0.47 h). The mean systemic availability was estimated to be 99 +/- 29%. Tianeptine was eliminated from plasma with a half-life of 2.5 +/- 1.1 h, mainly via extrarenal route since its renal clearance averaged 0.38 +/- 0.47 ml.min-1. Plasma levels of metabolite MC5 were lower than those of the parent drug but decreased with a longer half-life (7.2 +/- 5.7 h). Alcohol co-administration decreased tianeptine absorption rate and lowered tianeptine plasma levels by about 30% but did not affect those of the MC5 metabolite.     

The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans

OBJECTIVE: Inflammation induced by Escherichia coli lipopolysaccharide alters the clearance of several hepatically eliminated drugs. Extensive rat liver research has shown CYP2E1 down-regulation after lipopolysaccharide administration. To further investigate this phenomenon in humans, lipopolysaccharide was administered to healthy male volunteers and chlorzoxazone was used as a CYP2E1 probe drug. METHODS: Twelve healthy men were given 500 mg oral chlorzoxazone after two daily lipopolysaccharide doses (20 endotoxin units/kg/day) and again after administration of saline solution in this balanced crossover study. Serum and urine chlorzoxazone and 6-hydroxychlorzoxazone were quantified, as well as cytokine and C-reactive protein levels. RESULTS: Lipopolysaccharide produced the expected induction of the acute-phase response shown by elevations in tumor necrosis factor, interleukin-6, C-reactive protein, and temperature. Lipopolysaccharide treatment failed to produce a significant change in the chlorzoxazone oral clearance (4.4 +/- 0.9 mL/min/kg for lipopolysaccharide versus 4.2 +/- 1.4 mL/min/kg for control) or the 6-hydroxychlorzoxazone formation clearance (2.8 +/- 0.65 mL/min/kg for lipopolysaccharide versus 2.5 +/- 0.9 mL/min/kg for control). The high intersubject variabilities in oral clearance and formation clearance were not accounted for by changes in protein binding, cytokine, or C-reactive protein values. In contrast, a significant increase in the 6-hydroxychlorzoxazone glucuronide renal clearance was observed (7.5 +/- 1.37 mL/min/kg for lipopolysaccharide versus 6.1 +/- 1.7 mL/min/kg for control). CONCLUSIONS: This study showed that the inflammatory response to lipopolysaccharide (20 endotoxin units/kg/day for 2 days) in humans does not consistently alter chlorzoxazone hepatic metabolism. However, the significant increase in renal clearance of the glucuronidated metabolite suggests that renal tubular secretion may be increased in humans with acute endotoxemia.     

Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans

Abstract Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (> or =3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2-3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1-1.2 L/kg), larger for fexofenadine (5.4-5.8 L/kg) and particularly large for desloratadine (approximately 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (approximately 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84-95% (faeces) and 8-15% (urine) for 14C-mizolastine. The absolute bioavailability is 50-65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions.