The pharmacokinetics of the enantiomers of mexiletine in humans

1. This study examined the pharmacokinetics of the enantiomers of mexiletine in five healthy subjects who were each given a single, 300 mg, oral dose of racemic mexiletine hydrochloride. 2. The time course of the concentration ratio between the R(-) and the S(+) enantiomers (R/S) in plasma showed a progressive decrease, with a mean +/- S.D. ratio of 1.37 +/- 0.11 at 1 h and 0.64 +/- 0.11 at 48 h. Similarly, the R/S ratios in urine were 1.38 +/- 0.42 and 0.55 +/- 0.12 at 1 h and 72 h, respectively. 3. The terminal elimination half-life of S(+)mexiletine was 11.0 +/- 3.80 h, which was significantly greater (P less than 0.05) than that of the R(-) enantiomer, 9.10 +/- 2.90 h. S(+)Mexiletine also showed a significantly greater apparent volume of distribution (P less than 0.01) and renal clearance (P less than 0.05) than R(-)mexiletine. There was no significant difference in the apparent oral total drug clearance of the enantiomers. 4. The disposition of mexiletine enantiomers in man was stereoselective, and the differences observed between the enantiomers may be due largely to differences in their serum protein binding.     

Disposition of flurbiprofen in man: influence of stereochemistry and age

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4'-hydroxy- metabolite in serum and the drug, 4'-hydroxy- and 3'-hydroxy-4'-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p<0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4'-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p<0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p<0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4'-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p<0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p<0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.     

Pharmacokinetics and pharmacodynamics of glyburide in young and elderly nondiabetic adults

The pharmacokinetics and pharmacodynamics of glyburide were studied in elderly and young nondiabetic adults. Healthy nondiabetic men and women 18-40 years of age (young subjects) and 60-85 years of age (elderly subjects) were recruited. After an overnight fast, the subjects were given a baseline glucose tolerance test (GTT). The next day, again after a fast, each subject was given a 5-mg oral tablet of glyburide, and the GTT was performed one hour later. Serum glucose, serum insulin, and plasma glyburide concentrations were determined. Twenty elderly (mean +/- S.D. age, 65.7 +/- 5.3 years) male (n = 10) and female (n = 10) volunteers and 15 young (22.3 +/- 4.5 years) male volunteers were enrolled. Compared with the young subjects, the elderly subjects had slower glyburide absorption, as determined from a lower peak plasma concentration and smaller area under the plasma concentration-time curve from zero to four hours (AUC0-4). The elderly subjects also had a lower glyburide elimination rate constant and higher volume of distribution and a 52% higher free fraction. There was no difference in the glyburide AUC0-24 or AUC0-infinity or in oral clearance between the groups. The elderly group had greater increases in serum glucose and insulin concentrations after the baseline GTT. After glyburide administration, the elderly group had a smaller fractional decrease in the glucose AUC0-3 from the baseline GTT result than the young subjects. Linear regression analysis of the relationship between the fractional change in glucose concentration and the glyburide AUC0-4 showed significantly different slopes between the two groups. The aging process appears to affect the pharmacokinetics and pharmacodynamics of glyburide.     

Pharmacokinetics of M100240 and MDL 100,173, a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor, in healthy young and elderly volunteers

M100240 is an acetate thioester of MDL 100,173-a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor-in phase II development. The pharmacokinetics of M100240 and MDL 100,173 were compared in young and elderly subjects. Pharmacokinetic data were obtained from 12 young (ages 18-45 years, 10 male, 2 female) and 12 elderly (ages 65-85 years, 7 male, 5 female) healthy subjects in a parallel-group, open-label study. Following an overnight fast, subjects received a single 25-mg oral dose of M100240. Serial plasma concentrations of M100240 and MDL 100,173 were determined using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, and pharmacokinetic parameters were calculated with noncompartmental methods. Single-dose treatment with M100240 was well tolerated in both groups of subjects, with no clinically significant changes in vital signs, ECG recordings, or laboratory safety parameters. M100240 was rapidly absorbed and converted to MDL 100,173, with M100240 concentrations no longer detectable at 3 to 4 hours postdose in both groups. The pharmacokinetics of the pharmacologically active MDL 100,173 were similar for both groups. Although maximum concentrations of M100240 were generally higher in elderly versus young subjects (C(max) 0.48 ng/mL vs. 0.17 ng/mL), systemic availability of M100240 was quite low and variable with plasma, and this apparent difference in parent drug exposure is unlikely to have important clinical implications. No age-related differences in the pharmacokinetic parameters of MDL 100,173 (C(max) 8.16 vs. 9.62 ng/mL, t(max) 1.25 vs. 1.5 h, AUC((0-last)) 81.6 vs. 72.2 ng x h/mL) were observed between young and elderly subjects, respectively. In conclusion, there are no age-related differences in the pharmacokinetics of MDL 100,173 between young and elderly subjects.     

Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.     

Stereoselective disposition of etodolac enantiomers in synovial fluid.

The synovial fluid (SF) uptake of the chiral nonsteroidal anti-inflammatory drug, etodolac, was studied in six arthritic patients, 2 hours (n = 1) or 12 hours (n = 5) after a single 200 mg dose of racemate. Marked stereoselectivity was seen in both SF and plasma; concentrations of pharmacologically inactive R-etodolac were up to 10-fold greater than active S-etodolac. Concentrations of S-etodolac were greater in SF than in plasma (SF:plasma ratio = 1.98 +/- 0.8): No such difference was seen for R-etodolac (SF:plasma = 0.91 +/- 0.3). Considerable concentrations of conjugated enantiomers were present in SF. In vitro equilibrium dialysis studies in drug-spiked samples showed that the unbound fraction of both enantiomers in SF was greater than in plasma; both fluids bound R more extensively than S etodolac. Therapeutically active S-etodolac has greater concentrations in synovial fluid than plasma during the post-distributive phase, which may be of possible clinical relevance.     

Effect of aging on the pharmacokinetics of acebutolol enantiomers.

Acebutolol (AC) is a chiral beta-blocker that is metabolized to an equipotent chiral metabolite, diacetolol (DC). A stereoselective disposition of AC and DC enantiomers has recently been reported in young healthy subjects. As many physiologic properties affecting drug disposition are progressively altered with increasing age, the effect of aging on the pharmacokinetics of AC and DC enantiomers were investigated in nine subjects ranging from 60 to 75 years after administration of an oral 200-mg dose of racemic AC. Increasing age resulted in a significant prolongation of the elimination t1/2s of R- (r = 0.913) and S-DC (r = 0.811). Also, the S:R ratios of AC urinary excretion (sigma Xu) of enantiomers was significantly correlated with age (r = 0.677). Contribution of declining renal function to age-associated pharmacokinetics changes was subsequently examined. Renal clearance and cumulative urinary excretion of both AC and DC enantiomers were positively correlated with creatinine clearance. In addition, declining creatinine clearance was associated with a subsequent decline in the enantiomer S:R ratio of AC in plasma (AUC S:R, r = 0.807) and urine (sigma Xu S:R r = 0.807). Similarly, a progressive decline in the S:R ratio of DC collected in urine was evident (r = 0.689). Age-related changes in the enantiomers ratios may suggest that an active stereoselective pathway such as renal tubular secretion or nonrenal excretion may be affected in the elderly.     

The effect of age on the pharmacokinetics of enoxacin

Summary We have studied the pharmacokinetics of enoxacin in two groups of subjects, 10 young (18–45 years) and 10 elderly adults (>65 years) after a single oral dose of enoxacin (600 mg). Enoxacin was absorbed rapidly, peak plasma concentrations being reached within two hours in both groups. However, the peak plasma concentration of enoxacin was significantly higher in the elderly than in the young adults. The area under the concentration-time curve extrapolated to infinity was also significantly greater in the elderly compared with the young subjects, and the apparent renal clearance was significantly less in the elderly than in the young adults. Consequently, the urinary elimination of unchanged enoxacin was significantly reduced in the elderly. The apparent volume of distribution in the elderly was significantly less than in the young adults. The elimination half-time of enoxacin was similar in the two groups.     

Enantioselective pharmacokinetics of etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism.

The nonsteroidal anti-inflammatory agent etodolac (ET) exhibits stereoselectivity in its pharmacokinetics following administration to humans and rats. To underline the factors responsible for this stereoselectivity, the tissue distribution, in vitro tissue binding, and microsomal metabolism of ET enantiomers were studied in the rat. Following iv administration of racemic ET, the S:R AUC ratios in tissues were stereoselective, and different from that in plasma. Binding of enantiomers to tissues was stereoselective, although it did not relate well with in vivo tissue distribution. Rather, the tissue distribution of enantiomers appeared to be better explained by the unbound fractions of enantiomers in plasma. With respect to in vitro glucuronidation by liver microsomes, the Vmax of S-ET was 3.4-fold greater than that of R-ET; the enantiomers possessed similar Km. There appeared to be stereoselectivity in the oxidative metabolism of ET enantiomers by liver and kidney microsomes, in favor of the R-enantiomer. The lower AUC in rat plasma of pharmacologically active S-ET as compared with its antipode is due to its relatively greater distribution to tissues, owing to a lesser degree of binding to plasma proteins, and to its higher rate of glucuronidation.     

Stereoselective pharmacokinetics of propafenone and its major metabolites in healthy Chinese volunteers.

The stereoselective pharmacokinetics of propafenone (PPF) and its active metabolite 5-hydroxypropafenone (5-OHP) as well as their glucuronide and sulfate conjugates have been investigated, in order to clarify the relationship between metabolism and stereoselective disposition of PPF in humans. After oral administration of 300 mg racemic PPF hydrochloride to 10 healthy Chinese subjects, the areas under the plasma concentration-time curves (AUCs) for (S)-PPF were significantly higher (S/R ratio, 1.50+/-0.17) and the apparent oral clearance significantly lower (S/R ratio, 0.68+/-0.07) than those parameters for (R)-PPF. In contrast, the AUCs of PPF glucuronide (PPF-G) were lower for (S)-PPF-G than for the (R)-enantiomer (S/R ratio, 0.83+/-0.12). The partial clearance of (S)-PPF by glucuronidation pathway was lower than that of (R)-PPF and the enantiomeric ratio was 0.62+/-0.04. The t(max) values of PPF glucuronide diastereoisomers showed no statistically significant differences between each other, but were much shorter than the corresponding values of the parent drug, implying that glucuronidation may be the 'first-choice' pathway in presystemic metabolism of PPF. Glucuronidation of 5-OHP favored the (S)-enantiomer, whereas the sulfation showed a large preference for the (R)-enantiomer. After beta-glucuronidase hydrolysis, no significant differences were observed in AUCs between 5-OHP enantiomers (including unconjugated and conjugated 5-OHP). The results suggest that the significant difference in disposition between PPF enantiomers may be, at least in part attributed to stereoselective metabolism in the glucuronidation pathway.     

Pharmacokinetics of loprazolam and its principal metabolite in young subjects and elderly hospital patients

1. The pharmacokinetics of loprazolam and its principal pharmacologically active metabolite, the piperazine N-oxide, were compared in young subjects (aged 21-25 years) and elderly patients (aged 63-86 years) following single oral evening doses (0.5 mg and 1 mg). 2. Plasma loprazolam was assayed by a specific h.p.l.c./g.c. method. The N-oxide metabolite was assayed by gas chromography. 3. Mean times to peak plasma concentration of loprazolam did not differ significantly between young and elderly subjects and ranged from 1.6-2.7 h. There was, however, a longer mean time to peak concentration of the N-oxide metabolite in the elderly but this was only statistically different after the 0.5 mg dose (4.5 mg young, 6.4 h elderly). 4. Mean peak plasma concentrations of loprazolam did not differ significantly between young and elderly nor did plasma concentrations of the N-oxide metabolite. 5. Although the mean elimination half-life of loprazolam was not statistically significantly different between young and elderly subjects (range 10.9-16.0 h) there was a trend towards somewhat longer half-lives in the elderly. Furthermore, there was a small but significant increase in the half-life of the N-oxide metabolite in the elderly after the 1 mg dose from 11.7 h to 16.7 h. 6. The areas under the plasma concentration time curves for both loprazolam and its N-oxide were greater in the elderly being some 50-68% (mean 132.0 and 111.5 ng/ml h) above those found in young subjects (mean 89.8 and 66.0 ng/ml h).(ABSTRACT TRUNCATED AT 250 WORDS)     

Absolute bioavailability of reboxetine enantiomers and effect of gender on pharmacokinetics

The absolute bioavailability of reboxetine enantiomers was assessed in six male and six female volunteers. In a two-way crossover study, subjects received 1.0 mg reboxetine orally and 0.3 mg reboxetine as an intravenous bolus. The R,R(-) and S,S(+) enantiomers in serial plasma and urine samples were determined by a validated LC-MS-MS method. There were no significant differences between treatments for clearance or dose-corrected AUC(0-infinity) values. The absolute bioavailability was 0.919 and 1.02 for R,R(-) reboxetine and S,S(+) reboxetine, respectively. A secondary objective of the study was to assess gender effects on pharmacokinetics of the enantiomers. Significant differences in volume of distribution between genders were observed, but differences in weight-corrected volumes were not significant. Weight-corrected systemic clearance and oral clearance tended to be lower in males, but this difference reached statistical significance only for weight-corrected oral clearance of R,R(-) reboxetine. C(max) after oral administration was 40 and 48% higher in women than men for R,R(-) reboxetine and S,S(+) reboxetine, respectively. These results indicate that reboxetine enantiomers are well absorbed after oral administration and that little first-pass metabolism occurs. There are no clinically significant effects of gender on the pharmacokinetics of reboxetine enantiomers.     

Pharmacokinetics of etodolac enantiomers in the rat after administration of phenobarbital or cimetidine.

The influences of phenobarbital and cimetidine on the pharmacokinetics of etodolac enantiomers were studied in male Sprague-Dawley rats. Phenobarbital caused significant reductions in the AUC of both the active S-enantiomer (24%) and the inactive R-enantiomer of etodolac (26%), and an increase in the urinary excretion of glucuronidated S-etodolac. In bile duct-cannulated rats the initial biliary recoveries of the acyl-glucuronidated etodolac enantiomers were not affected by phenobarbital. In vitro, phenobarbital caused no changes in the hepatic microsomal net glucuronidation of etodolac enantiomers after phenobarbital, although it did result in significant increases in the apparent oxidative metabolism of both enantiomers. Therefore, phenobarbital seems to cause an enhanced CL of etodolac by induction of hepatic non-conjugative metabolism. Cimetidine had no discernible effect on the pharmacokinetics of etodolac enantiomers.     

The single-dose pharmacokinetics of the novel CCK1 receptor antagonist, dexloxiglumide, are not influenced by age and gender

OBJECTIVE: The effects of age and gender on the single-dose pharmacokinetics of dexloxiglumide, a selective cholecystokinin (CCK1-subtype) receptor antagonist, were assessed in healthy young and elderly male and female subjects. METHODS: In total, 24 males and 24 females (12 young and 12 elderly subjects per gender group) received a single oral dose of 200 mg dexloxiglumide under fasted conditions. Mean (range) ages were 23.8 (18 - 32) and 71.3 (66 - 88) years for young and elderly subjects, respectively. Analysis of covariance (ANCOVA) with age group and gender as factors and body weight as a covariate was performed on the dexloxiglumide pharmacokinetic parameters of peak plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC). The p values obtained from ANCOVA were considered for the assessment of age and gender effects. RESULTS: A small (approximately 18%) but statistically significant (p < or = 0.036) increase in the area under the plasma concentration-time curve from 0 to time of last quantifiable concentration (AUC(0-t) and the area under the plasma concentration-time curve from 0 to infinity (AUC(0-infinity)) in elderly compared to young subjects was noted. Given the lack of age effects on the other pharmacokinetic parameters of dexloxiglumide, this limited difference is unlikely to be clinically relevant. Without the adjustment for body weights, female subjects exhibited mean C(max) and AUC values approximately 26% and 36% higher than male subjects; however, these exposure differences did not reach statistical significance (p > 0.05) following ANCOVA analysis with body weight as a covariate. Likewise, there were no statistically significant differences (p > 0.05) observed for any other pharmacokinetic parameters between young and elderly and between male and female groups. CONCLUSIONS: Dose adjustments based on age and gender are not necessary. Dexloxiglumide administration was safe and well tolerated in these subjects.     

Sibutramine pharmacokinetics in young and elderly healthy subjects

Objective: To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. Methods: This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. Results: The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in k_el. Conclusions: The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly. Received: 8 June 1998 / Accepted in revised form: 18 September 1998     

Pharmacokinetics of loprazolam and its principal metabolite in young subjects and elderly hospital patients

1. The pharmacokinetics of loprazolam and its principal pharmacologically active metabolite, the piperazine N-oxide, were compared in young subjects (aged 21–25 years) and elderly patients (aged 63–86 years) following single oral evening doses (0.5 mg and 1 mg).

2. Plasma loprazolam was assayed by a specific h.p.l.c./g.c. method. The N-oxide metabolite was assayed by gas chromography.

3. Mean times to peak plasma concentration of loprazolam did not differ significantly between young and elderly subjects and ranged from 1.6–2.7 h. There was, however, a longer mean time to peak concentration of the N-oxide metabolite in the elderly but this was only statistically different after the 0.5 mg dose (4.5 mg young, 6.4 h elderly).

4. Mean peak plasma concentrations of loprazolam did not differ significantly between young and elderly nor did plasma concentrations of the N-oxide metabolite.

5. Although the mean elimination half-life of loprazolam was not statistically signiticantly different between young and elderly subjects (range 10.9–16.0 h) there was a trend towards somewhat longer half-lives in the elderly. Furthermore, there was a small but significant increase in the half-life of the N-oxide metabolite in the elderly after the 1 mg dose from 11.7 h to 16.7 h.

6. The areas under the plasma concentration time curves for both loprazolam and its N-oxide were greater in the elderly being some 50–68% (mean 132.0 and 111.5 ng/ml h) above those found in young subjects (mean 89.8 and 66.0 ng/ml h).

7. Despite these changes the maximum accumulation ratio predicted from these single dose studies would be 1.16 in the young and 1.40 h in the elderly, assuming once nightly dosing.     

Clinical pharmacokinetics of ketoprofen and its enantiomers

Ketoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only the S-enantiomer possessing beneficial pharmacological activity, all ketoprofen preparations to date are marketed as the racemate. Ketoprofen exhibits little stereoselectivity in its pharmacokinetics. The enantiomers have similar plasma time-courses and do not seem to interact with one another. Hence, the data generated using nonstereospecific assays may be used to explain the pharmacokinetics of individual enantiomers. The absorption of ketoprofen is rapid and almost complete when given orally. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase half-life of ketoprofen (1 to 3h). They may also decrease local gastrointestinal side effects. Although with these preparations the peak plasma drug concentration is reduced and time to peak is prolonged, the bioavailability is the same as that with regular release counterparts. Ketoprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, the proposed site of action of NSAIDs. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolite. There is about 10% R to S inversion upon oral administration. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The excretion of conjugates is closely tied to renal function; accumulation of conjugates occurs in the elderly, but not in young subjects or patients. Significant drug interactions have been demonstrated for probenecid, aspirin and methotrexate. There appears to be circadian variation, particularly in the absorption of ketoprofen. The relationship between concentration and anti-inflammatory effect has yet to be elucidated for this drug.     

Stereoselective pharmacokinetics of oral nitrendipine in elderly hypertensive patients with normal and impaired renal function

Summary The pharmacokinetics of the enantiomers of nitrendipine has been studied in seven elderly patients with chronic renal failure (CRF) and in six control subjects (mean creatinine clearance 30 and 97 ml·min^–1 respectively). Racemic nitrendipine 20 mg was given once daily for seven days and the pharmacokinetics of the enantiomers over the last dosage interval were determined using a stereospecific assay.In both groups nitrendipine exhibited stereoselective pharmacokinetics (AUC, C_max), but the half-lives of the enantiomers did not differ in individual subjects. As an index of stereoselectivity, the mean S/R ratio of AUCs in control subjects (2.07) was not significantly different from the ratio in patients with CRF (2.68).The mean AUCs of (S)- and (R)-nitrendipine during the last dosage interval were increased in CRF by 132% and 85%, respectively. The observed doubling of the half-lives and the increases in C_max did not reach significance because of the large variability in each group.Thus, the pharmacokinetics of oral nitrendipine is altered in CRF, but there was no change in the stereoselectivity of its pharmacokinetics.     

Pharmacokinetics of ketoprofen enantiomers in young and elderly arthritic patients following single and multiple doses

Ketoprofen (KT), a chiral nonsteroidal anti-inflammatory drug (NSAID), is marketed and used as a racemic mixture. In healthy volunteers, negligible differences have been reported between the plasma time courses of KT enantiomers. Using a stereospecific high-performance liquid chromatographic (HPLC) assay measuring (R)- and (S)-KT in plasma and urine, pharmacokinetics of the enantiomers following single (50 mg) and then multiple (50 mg every 6 h for 3 d) doses were delineated in nine young and nine elderly arthritic patients. There were no significant differences between pharmacokinetic indices calculated after single and multiple doses, or between the two groups. In plasma, there were no significant differences between intact enantiomers in either patient group. However, significantly more conjugated (S)-KT was found in elderly patient plasma. Similar to findings in healthy volunteers, elimination of conjugated KT in both patient groups was more extensive for the (S)-, as compared with the (R)-isomer. It is suggested that age-dependent impaired elimination of conjugated (S)-KT, along with preferential biliary excretion of conjugated (R)-KT, is responsible for these observations.     

Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects

This open-label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (>or=65 years) and 28 young (18-45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300-mg oral dose of aliskiren. In elderly compared with young subjects, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n=16) and >or=75 years (n=13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.