The effect of rifampin administration on the disposition of fexofenadine

OBJECTIVE: Our objective was to assess the effect of rifampin (INN, rifampicin) on the pharmacokinetics of fexofenadine and to assess the influence of advanced age and sex. METHODS: Twelve young volunteers (6 men and 6 women; age range, 22 to 35 years) and twelve elderly volunteers (6 men and 6 women; age range, 65 to 76 years) received a 60-mg oral dose of fexofenadine before and after treatment with 600 mg of oral rifampin for 6 days. Blood and urine were collected for 48 hours and assayed for fexofenadine, azacyclonol, and rifampin by HPLC with either fluorescence or mass spectrometry detection. RESULTS: All of the groups had a significant increase (P <.05) in the oral clearance of fexofenadine after rifampin treatment: young men, 2955 +/- 1516 versus 5524 +/- 3410 mL/min; young women, 2632 +/- 996 versus 7091 +/- 5,379 mL/min; elderly men, 1760 +/- 850 versus 4608 +/- 1159 mL/min; and elderly women, 2210 +/- 554 versus 4845 +/- 1600 mL/min. The peak serum concentration of fexofenadine was also significantly reduced (P <.05) by rifampin treatment: young men, 77 +/- 31 versus 52 +/- 17 ng/mL; young women, 72 +/- 19 versus 36 +/- 14 ng/mL; elderly men, 106 +/- 42 versus 52 +/- 14 ng/mL; elderly women, 76 +/- 23 versus 46 +/- 19 ng/mL. Half-life (150 to 230 minutes), time to maximum concentration (130 to 205 minutes), renal clearance (95 to 153 mL/min), and fraction unbound (2.9% to 3.7%) of fexofenadine showed no significant difference between control and treatment. The amount of azacyclonol, a CYP3A4 mediated metabolite of fexofenadine, eliminated renally increased on average 2-fold after rifampin dosing; however, this pathway accounted for less than 0.5% of the dose. No effect of age or sex on fexofenadine disposition or serum trough rifampin concentration (0.2 microg/mL to 1.8 microg/mL) was observed before or after rifampin treatment. CONCLUSION: This study showed that rifampin effectively increased fexofenadine oral clearance and that this effect was independent of age and sex. We conclude that the cause of the increased oral clearance of fexofenadine is a reduced bioavailability caused by induction of intestinal P-glycoprotein.     

Theophylline pharmacokinetics in normal elderly subjects

The effect of age on theophylline kinetics was examined in six normal young men and six elderly men. There were no age-associated differences in theophylline volume of distribution, total clearance, or t1/2. The unbound fraction of theophylline was significantly raised in the elderly (mean 77.7% vs. 62.3%, p less than 0.001) and was correlated with the serum albumin level (r = -0.7, p less than 0.01). Theophylline nonrenal clearance was not changed, but the total unbound clearance was significantly reduced in the elderly subjects as compared with the young ones (mean 0.744 vs. 1.085 ml/min/kg, p less than 0.05). Creatinine clearance was reduced in the elderly and was significantly correlated with unbound renal clearance (r = 0.6, p less than 0.04). There were no age-related differences in the urinary excretion of theophylline, 1-methyluric acid, 3-methylxanthine, or 1,3-dimethyluric acid. However, significant reduction in unbound renal theophylline clearance (p less than 0.002) as well as the unbound metabolic clearance of 1,3-dimethyluric acid (p less than 0.03), 3-methylxanthine (p less than 0.04), and 1-methyluric acid (p less than 0.02) were observed in the elderly subjects. These observations indicate that both renal and metabolic elimination processes for theophylline are less active in the normal elderly.     

Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers.

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 young and 12 elderly). Each volunteer received single 0.5-, 1-, and 2-g doses of cefmetazole administered intravenously over 5 min according to a three-way crossover design. Serial plasma and urine samples were collected over a 24-h period following dosing and assayed for cefmetazole by a high-performance liquid chromatography method. Results of the dose proportionality portion of the study indicated that cefmetazole pharmacokinetics are linear and proportional with dose in both age groups. Comparisons of pharmacokinetic parameters between the young and elderly groups indicated that the systemic clearance was significantly lower in elderly than in young volunteers (92.4 versus 112 ml/min). Additionally, creatinine clearance was significantly lower in elderly (74.1 ml/min) than in young (92.9 ml/min) subjects. No significant differences between age groups were observed for volume of distribution, urinary recovery, terminal half-life, nonrenal clearance, or renal clearance, although half-life was slightly prolonged in elderly volunteers relative to that in young volunteers (1.54 versus 1.34 h), and renal clearance was slightly lower in elderly than in young volunteers (83.7 versus 96.1 ml/min). Both systemic and renal clearance were significantly correlated with creatinine clearance. These results indicate that the observed age-related differences in the pharmacokinetics of cefmetazole are most likely due to differences in renal function between the two age groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population.     

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.     

The effect of age,sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity

BACKGROUND: The relative susceptibility of intestinal and hepatic cytochrome P450 (CYP) 3A to induction by rifampin (INN, rifampicin), as a function of age and sex, was investigated with the CYP3A substrate midazolam. METHODS: Fourteen young women (mean age, 26 +/- 4 years), 14 young men (mean age, 27 +/- 4 years), 14 elderly women (mean age, 72 +/- 5 years), and 10 elderly men (mean age, 70 +/- 4 years) received simultaneous intravenous doses (0.05 mg/kg over a 30-minute period) and oral doses of midazolam (3-8 mg of a stable isotope, (15)N(3)-midazolam) before and after 7 days of rifampin dosing (600 mg once daily in the evening). Serum and urine samples were assayed for midazolam, (15)N(3)-midazolam, and metabolites by liquid chromatography-mass spectrometry. RESULTS: No significant difference (P > or =.05) in the baseline systemic and oral clearance of midazolam was observed between male and female or young and old volunteers. Rifampin significantly (P <.0001) increased the systemic and oral clearance of midazolam from 0.44 +/- 0.2 L. h/kg and 1.56 +/- 0.8 L x h/kg to 0.96 +/- 0.3 L x h/kg and 34.4 +/- 21.2 L x h/kg, respectively. Likewise, the oral clearance of midazolam was significantly (P <.0001) increased in women and men, from 1.64 +/- 0.87 L x kg/h and 1.46 +/- 0.7 L x kg/h to 28.4 +/- 13.2 L x kg/h and 41.6 +/- 26.5 L x kg/h, respectively. A significant (P =.0023) effect of sex was noted in the extent of induction of the oral clearance of midazolam, being greater in men than in women. In contrast, the extent of midazolam systemic clearance induction was greater in women than in men (P =.0107). Age did not influence the extent of intestinal and hepatic CYP3A induction as determined by the oral and systemic clearance of midazolam. Rifampin dosing significantly (P <.0001) reduced the oral availability by 88%, from 0.32 +/- 0.13 to 0.04 +/- 0.02. Correspondingly, hepatic and intestinal availabilities were significantly (P <.0001) reduced after rifampin administration. After rifampin, the correlation coefficient for the relationship between oral availability and intestinal availability was significantly (P <.0001) reduced from 0.96 to 0.67, which reflects the increasing contribution of hepatic extraction to the determination of midazolam oral availability. A significant nonlinear inverse relationship was observed between the percent change in systemic clearance of midazolam and the initial baseline midazolam systemic clearance (r = -0.68, N = 52, P <.0001). Likewise, a significant inverse relationship was observed between the percent change in oral clearance and the baseline oral clearance (r = -0.39, N = 52, P =.0041). A significant inverse relationship between the ratio of hepatic intrinsic clearance in the presence of rifampin to that in the absence of rifampin and the corresponding ratio of intestinal intrinsic clearance was observed (Spearman correlation coefficient [r] = -0.68, P <.0001) and indicates that in a given individual the extent of induction was high at either the hepatic or the intestinal site but not both. CONCLUSION: Sex-related differences exist in the extent of intestinal and hepatic CYP3A induction by rifampin. The extent of induction at hepatic and intestinal sites was inversely dependent and reflected the independent regulation of CYP3A expression at these sites. The large interindividual variation in the extent of induction is explained in part by the variation in baseline expression of CYP3A. Sex-related differences in response to CYP3A inducers will be substrate-dependent and reflect the relative contribution of hepatic and intestinal sites of metabolism.     

Effects of age and sex on piroxicam disposition

Piroxicam kinetics were studied after a single, oral, 20-mg capsule was taken by 12 young (six women, six men) and 13 elderly (seven women, six men) healthy subjects. Plasma samples were drawn for 216 hr after dosing. Plasma protein binding was studied in vitro by equilibrium dialysis and piroxicam concentrations were measured by HPLC with ultraviolet detection. The apparent volume of distribution was smaller in elderly women (7.8 +/- 0.4 l) than in young men (11.3 +/- 0.3 l) and elderly men (10.8 +/- 0.8 l). There were no such differences when the apparent volume of distribution was normalized for total body weight. There was a strong correlation between total body weight and apparent volume of distribution in all subjects (r = 0.83). Plasma protein binding of piroxicam ranged from 98.90% to 99.54% bound and was not affected by age or sex. Piroxicam body clearance in elderly women (0.026 +/- 0.002 ml/min/kg) was approximately 33% lower than in young women (0.039 +/- 0.003 ml/min/kg). This difference was reflected in different t1/2s of 61.7 and 44.9 hr. Predicted steady-state plasma piroxicam concentrations were 5.7 micrograms/ml in young women, 5.4 micrograms/ml in young men, 5.7 micrograms/ml in elderly men, and 9.3 micrograms/ml in elderly women. The high value in elderly women results from the lower piroxicam body clearance and total body weight. Our data suggest that healthy elderly women eliminate piroxicam at a slower rate than healthy young women. The clinical significance of these data needs to be assessed in patients.     

Absence of age and gender effects on the pharmacokinetics of a single 500-milligram oral dose of levofloxacin in healthy subjects.

The influence of age and gender on the pharmacokinetics of levofloxacin in healthy subjects receiving a single oral 500-mg dose of levofloxacin was investigated in this parallel design study. Six young males (aged 18 to 40 years), six elderly males (aged > or = 65 years), six young females (aged 18 to 40 years), and six elderly females (aged > or = 65 years) were enrolled and completed the study. The study reveals that the bioavailability (rate and extent) of levofloxacin was not affected by either age or gender. In both age (young and elderly) and gender (male and female) groups of subjects, peak concentrations in plasma were reached at approximately 1.5 h after dosing; renal clearance of levofloxacin accounted for approximately 77% of total body clearance, and approximately 76% of the administered dose was recovered unchanged in urine over the 36 h of collection. The apparent differences in the calculated pharmacokinetic parameters for levofloxacin between the age groups (young versus elderly) and between the gender groups (males versus females) could be explained by differences in renal function among the subjects. A single dose of 500 mg of levofloxacin administered orally to both young and old, male and female healthy subjects was found to be safe and well tolerated. As the differences in levofloxacin kinetics between the young and the elderly or the males and the females are limited and are mainly related to the renal function of the subjects, dose adjustment based on age or gender alone is not necessary.     

Pharmacokinetics of nicotine in healthy elderly people

BACKGROUND: Mortality hazards of smoking extend well into later life; this suggests that smoking cessation will continue to improve life expectancy in older people. The pharmacology and pharmacokinetics of nicotine have not been studied in elderly subjects. Drug disposition and pharmacodynamic responsiveness to nicotine may change with age, and conclusions founded on data from studies of younger populations may not apply to elderly populations. Our aim was to assess the pharmacokinetics of nicotine in healthy elderly subjects compared with healthy adults. METHODS: Twenty healthy elderly subjects (age, 65-76 years) and 20 healthy adult subjects (age, 22-43 years) were given an intravenous infusion of 0.028 mg/kg of nicotine over 10 minutes. Nicotine and cotinine concentrations were measured in plasma and urine. Heart rate and blood pressure were monitored. RESULTS: For most adult and elderly subjects nicotine distributed according to a two-compartment system. Even though there was a large interindividual variation within and overlap between groups, nicotine total clearance (-23%), nonrenal clearance (-21%), renal clearance (-49%), volume of central compartment (-37%), volume of distribution at steady state (-17%), and cotinine renal clearance (-18%) were statistically significantly decreased in elderly subjects compared with adults. Maximal heart rate response to nicotine was decreased in the elderly subjects (-29%). CONCLUSION: Even though statistically significant differences were observed, the disposition of nicotine does not seem to be changed to a clinically important extent in elderly subjects compared with younger adults.     

Retigabine, the specific KCNQ channel opener, blocks ectopic discharges in axotomized sensory fibres

The M-current has been proposed as a potential target for analgesia under neuropathic pain conditions. M-currents and/or their molecular correlates, KCNQ proteins, have been demonstrated in key elements of the nociceptive system including spinal and dorsal root ganglion neurons. Here we demonstrate that retigabine, a selective KCNQ channel opener, applied at neuromatose endings modulates the excitability of axotomized fibres inhibiting ectopic discharges. Responses to mechanical and chemical stimulation were obtained from intact and previously axotomized Adelta- and C-fibres using in vitro preparations and extracellular electrophysiological recording techniques. Application of retigabine (10 microM) produced an estimated approximately 80% reduction in the number of discharges produced by mechanical and chemical stimulation of most axotomized fibres tested (24/27). The electrical threshold of stimuli applied to the neuroma was found to increase in the presence of retigabine (+17.5+/-2.3%) and to decrease in the presence of a high potassium medium (-16.5+/-3.7%). This indicates that retigabine produces a hyperpolarization and a subsequent reduction of the excitability in aberrant sensory endings. Application of XE-991 (10 microM), a KCNQ channel blocker, had no effect on responses to stimulation of the neuroma but blocked the effects of retigabine indicating a specific involvement of KCNQ channels. In contrast to the strong effects on ectopic discharges, retigabine did not change responses to stimulation recorded from intact receptors. Results indicate that KCNQ channel opening at axotomized endings may constitute a novel and selective mechanism for modulation of some neuropathic pain symptoms.     

The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat

Homo- and heteromeric complexes of KCNQ channel subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K(+) current with a well established role in control of neural excitability. We investigated the effect of KCNQ channel modulators on the activity of dopaminergic neurons in vitro and in vivo in the rat ventral mesencephalon. The firing of dopaminergic neurons recorded in mesencephalic slices was robustly inhibited in a concentration-dependent manner by the KCNQ channel opener N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester (retigabine). The effect of retigabine persisted in the presence of tetrodotoxin and simultaneous blockade of GABA(A) receptors, small-conductance calcium-activated K(+) (SK) channels, and hyperpolarization-activated (I(h)) channels, and it was potently reversed by the KCNQ channel blocker 4-pyridinylmethyl-9(10H)-anthracenone (XE991), indicating a direct effect on KCNQ channels. Likewise, in vivo single unit recordings from dopaminergic neurons revealed a prominent reduction in spike activity after systemic administration of retigabine. Furthermore, retigabine inhibited dopamine synthesis and c-Fos expression in the striatum under basal conditions. Retigabine completely blocked the excitatory effect of dopamine D(2) autoreceptor antagonists. Again, the in vitro and in vivo effects of retigabine were completely reversed by preadministration of XE991. Dual immunocytochemistry revealed that KCNQ4 is the major KCNQ channel subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways. Collectively, these observations indicate that retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 channels.     

The influence of age and gender on the stereoselective metabolism and pharmacokinetics of mephobarbital in humans

In this clinical investigation, four groups of subjects (eight young women and eight young men [age range, 18 to 25 years], and eight elderly women and eight elderly men [greater than 60 years of age]) received single oral doses (400 mg) of racemic mephobarbital. The apparent total body clearance of R-mephobarbital was much greater and the elimination half-life was much shorter in the young men compared with the other three groups. This enantiomer displayed an age-dependent gender effect and a gender-dependent age effect in its metabolism. The apparent total body clearance of the S-enantiomer was much lower than that of the R-enantiomer in all subjects and did not differ between subject groups, although the elimination half-life was slightly but significantly shorter in young males. A consequence of these enantiomeric differences was an apparently enhanced stereoselectivity in the metabolism of mephobarbital in young men. These substantial influences of age and gender on the stereoselective disposition of mephobarbital are consistent with recent findings concerning the expression and regulation of cytochrome P450 enzymes.     

Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects.

The purpose of this investigation was to evaluate the effect of advanced age on the pharmacokinetics of cefetamet and its prodrug, cefetamet pivoxil. A secondary objective of this study was to assess the effect of food on the absorption of cefetamet pivoxil in the elderly. Twenty-four healthy subjects (twelve young and twelve elderly) received (in a Latin square design) a single-dose, 515-mg infusion of cefetamet, a single 1,000-mg oral dose of cefetamet pivoxil during fasted conditions, and a single 1,000-mg oral dose of cefetamet pivoxil 10 min after a standardized low-fat breakfast. Serial blood and urine samples were collected over a 36-h period and analyzed by high-performance liquid chromatography. Intravenous and oral pharmacokinetic parameters were obtained by using model-independent techniques. The systemic clearance and renal clearance of cefetamet were significantly lower (P less than 0.05) in elderly subjects compared with in young controls after intravenous administration. No significant difference was observed in the apparent volumes of distribution at steady state between the two groups. Consequently, half-life and mean residence time were prolonged. A trend toward a lower renal clearance/creatinine clearance ratio was observed in our elderly population. Oral clearance of cefetamet was only slightly reduced in our elderly subjects, consistent with an increase in plasma half-life. Otherwise, oral pharmacokinetic parameters were comparable between elderly and young subjects. Additionally, the same effects of food were observed on the absorption characteristics of cefetamet (no change in maximum concentration of drug in plasma and an increase in both time to maximum concentration of drug in plasma and bioavailability) in our elderly subjects as in our young volunteers. Age did not appear to alter the deesterification and bioavailability of cefetamet pivoxil. We conclude that the small reduction in the elimination of cefetamet in the elderly would not require dose adjustment for this population.     

Kinetics of prednisolone and endogenous cortisol suppression in the elderly

The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11 beta-hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 +/- 1.0 vs. 7.7 +/- 1.6 ml/min/kg, mean +/- SD; P less than 0.001) and renal (0.9 +/- 0.3 vs. 2.9 +/- 0.7 ml/min/kg; P less than 0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6 beta-hydroxyprednisolone (reflecting the activity of the 6 beta-hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.     

Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate

Sixty-one healthy men and women, aged 20 to 75 years, received single 0.25-mg doses of triazolam, a cytochrome P450 (CYP) 3A substrate benzodiazepine, and placebo in a double-blind crossover study. Among women, age had no significant effect on area under the triazolam plasma concentration curve (AUC) (Spearman r=0.14, P=.44) or clearance (r =-0.09, P=.62). Among men, AUC increased (r=0.43, P <.02) and clearance declined (r=-0.42, P <.02) with increasing age. Gender differences in triazolam kinetics were not apparent. Compared with placebo, triazolam impaired digit-symbol substitution test performance, increased observer-rated sedation, impaired delayed recall of information learned at 1.5 hours after dosing, and increased electroencephalographic beta amplitude. Among men, mean values of relative digit-symbol substitution test decrement (P <.002) and observer-rated sedation (P <.05) were significantly greater in elderly subjects compared with young subjects. Age-dependent differences among women reached significance for observer-rated sedation (P <.02). A combination of higher plasma levels and increased intrinsic sensitivity explained the greater pharmacodynamic effects of triazolam in elderly subjects. Although the findings are consistent with reduced clearance of triazolam in elderly men, individual variability was large and was not explained by identifiable demographic or environmental factors.     

Age and ceftriaxone kinetics

One gram ceftriaxone was injected at a constant rate in an intravenous infusion over 30 min to eight elderly subjects (mean age, 70.5 yr) and eight young subjects (mean age, 28.9 yr); the latter served as body weight-matched controls. Plasma and urine samples were collected in serial order for 48 hr and assayed for unchanged drug. Selected plasma samples were subjected to protein binding determinations by equilibrium dialysis. Statistical comparison of data for the old and young indicated no significant changes in means of (1) maximum plasma concentration (140 and 133 micrograms/ml); (2) elimination rate constant (0.078 and 0.093 hr-1) and elimination t1/2 (8.9 and 7.5 hr); (3) apparent volume of distribution (10.69 and 11.01 l); (4) plasma clearance (833 and 1023 ml/hr); (5) nonrenal clearance (515 and 606 ml/hr); and (6) percent dose excreted unchanged in urine (39.6 and 41.4). There was, however, a significant decrease in the renal clearance (318 and 416 ml/hr) and a significant increase in the plasma free fractions (0.157 and 0.136 at 100 micrograms/ml and 0.146 and 0.114 at 60 to 70 micrograms/ml) of ceftriaxone in elderly subjects. The 24% decrease in renal clearance in the elderly subjects corresponded to the 19% decrease in their creatinine clearance. Since the age-related changes in kinetics were relatively small, it is concluded that dosage adjustment is probably not necessary for elderly subjects requiring ceftriaxone.     

Pharmacokinetics of moxalactam in elderly subjects.

The pharmacokinetics of moxalactam were studied in 19 male volunteers 60 years of age or older with normal liver function tests and a creatinine clearance of greater than or equal to 60 ml/min. Moxalactam was administered in single or multiple intravenous or intramuscular doses. Rapid and complete intramuscular bioavailability was demonstrated in a subgroup of the study population. The mean plasma half-life was 2.9 +/- 0.8 h for intravenous doses and 3.5 +/- 0.9 h for intramuscular doses. Average renal clearances of 0.04 liters/kg per h accounted for 74.0 +/- 15.0% of total plasma clearance. Moxalactam plasma clearance showed a statistically significant (P less than 0.01) correlation with measured and calculated creatinine clearance. The major differences in moxalactam pharmacokinetics seen in the elderly appear to be related to diminishing renal function and highly variable nonrenal elimination. Creatinine clearance can be used in estimating moxalactam doses in the elderly without significant renal impairment, but recommendations for the use of serum creatinine as an estimation of renal function or drug half-life are not valid in this population group.     

Effects of age on meperidine disposition

Elderly patients appear to be more sensitive to meperidine than younger ones; however, the contributions of altered dynamic and kinetic factors are not clear. Accordingly, seven healthy normal men aged 60 to 79 yr were simultaneously given 25 mg meperidine HCl intravenously and the same dose of deuterium-labeled drug either orally or intramuscularly (deltoid). Blood and urine samples collected over 24 hr were analyzed by gas chromatography-mass spectrometry and kinetic data were compared to those previously obtained in a young cohort. Systemic clearance (8.61 +/- 2.22 ml/min/kg), apparent oral clearance (17.5 +/- 5.5 ml/min/kg), terminal t1/2 (6.98 +/- 1.86 hr), and the blood/plasma concentration ratio (0.97 +/- 0.12) in the elderly did not differ from those in younger subjects. In the elderly, however, the initial (2.4 +/- 0.8 l/kg) and the steady-state (4.6 +/- 0.9 l/kg) volumes of distribution were 300% and 135% values in the young. No age differences were found in absorption profiles or bioavailability after oral (F = 0.49 +/- 0.08) or intramuscular (F = 0.94 +/- 0.04) dosing. It appears that age-related alterations in drug disposition per se do not account for changes in clinical efficacy of meperidine in the elderly.     

Amitriptyline disposition in young and elderly normal men

The disposition of a single parenteral or single oral dose of amitriptyline was followed in seven young (mean age 22 yr, range 21 to 23) and five elderly (mean age 71 yr, range 62 to 81) healthy men. The mean systemic clearance did not change with age (10.8 +/- 2.1 ml/min/kg in elderly and 12.5 +/- 2.3 ml/min/kg in young subjects). Mean t 1/2 was longer in the older (21.7 +/- 2.9 hr) than in the younger group (16.2 +/- 6.1 hr) as a result of an increase in the volume of distribution (17.1 +/- 2.4 and 14.1 +/- 2.0 l/kg). The bioavailability and the fraction of the drug bound to plasma proteins did not change with age. Single doses of amitriptyline were not well tolerated clinically by either elderly or young subjects, which confirms the need for a gradual buildup in the therapeutic regimen and for close clinical surveillance of elderly depressed patients treated with amitriptyline.     

Trazodone kinetics: effect of age, gender, and obesity

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.     

Amantadine kinetics in healthy elderly men: implications for influenza prevention

Amantadine kinetics were investigated in 10 healthy elderly men 60 to 76 yr old. We calculated a dose that would yield the same trough steady-state plasma amantadine concentration (Cpss; 300 ng/ml) as a 200 mg/day dose taken by young healthy adults; this dose prevents influenza A virus infection and is well tolerated by this population. With a one-compartment open model, kinetic parameters were calculated after a single dose of 25, 50, or 75 mg or the same dose twice a day for 10.5 days. Peak concentration occurred 4.0 to 8.0 hr after dosing, but the calculated AUC was proportional to dose, indicating that relative bioavailability was independent of dose. This was supported by recovery of 88% of the single doses in urine. No change in apparent volume of distribution was found. Log trough Cpss increased with dose. Trough Cpss varied less than 300% for equivalent doses. There was first-order elimination of drug from plasma, with a median t1/2 of 28.9 hr (range 18.5 to 45.0 hr), and elimination was independent of dose and creatinine clearance. The median ratio of renal amantadine clearance to creatinine clearance was 2.07 (range 0.64 to 4.20), suggesting renal tubular secretion. Compared to data from healthy young adults, the t1/2 was doubled and renal drug clearance was diminished in elderly men. To achieve the target trough Cpss of 300 ng/ml, healthy older men must take amantadine at a dose of 1.4 mg/kg/day, and we suggest that this is a rational dose for evaluation of efficacy and safety for influenza A prophylaxis in this population.