Impaired sensitivity of the hypothalamo-pituitary-thyroid axis to the suppressant effect of dexamethasone in elderly subjects

It has been shown that glucocorticoids have a suppressant effect on the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in young men. To assess whether this effect of corticosteroids is also present in aged individuals, six young subjects (aged 26–32 years) and six elderly men (aged 68–75 years) underwent, in random order, at 1 week intervals, three TRH stimulation tests 30 min after IV administration of placebo and 2 mg and 4 mg dexamethasone phosphate. Elderly men showed higher basal plasma levels of TSH (P<0.02) and lower plasma levels of FT₃ (P<0.03) and FT₄ (P<0.01). The TSH response to TRH was significantly lower in aged subjects than in young ones (P<0.009). Moreover, 2 mg dexamethasone significantly blunted the TSH response to TRH in young men (P<0.0001), but not in the elders. The inhibitory effect of the glucocorticoid on the TRH-induced TSH secretion, in aged subjects, was evident only after 4 mg dexamethasone administration (P<0.0001). These data confirm that glucocorticoids have an inhibitory role on the thyrotropic axis and show, for the first time, that normal elderly men are hyporesponsive to this suppressant effect of corticosteroids.     

Prolactin response to sodium valproate in schizophrenics with and without tardive dyskinesia

Sodium valproate, a GABAergic agent (800 mg), and placebo were administered orally, as a single dose, to nine chronic schizophrenics with tardive dyskinesia (TD), seven chronic schizophrenics without TD and ten healthy controls, according to a double blind design. Blood samples were collected before and after drug administration, to determine plasma prolactin concentrations. Sodium valproate decreased plasma prolactin levels in healthy subjects (P<0.001) and in schizophrenic patients with TD (P<0.001), but not in chronic schizophrenics without TD. Moreover, in dyskinetic subjects, the maximum per cent decrease of plasma prolactin from basal value was positively correlated to the score of the abnormal involuntary movement scale (r=0.724, P<0.02). Although the neural or biochemical substrate underlying the different responses of plasma prolactin to sodium valproate in schizophrenics with and without TD remains unclear, these results provide the first neuroendocrine evidence able to differentiate dyskinetic subjects from those without TD within a schizophrenic population.     

Kinetics of atrial natriuretic peptide in young and elderly subjects

Summary To study the influence of age on the kinetics of atrial natriuretic peptide (ANP) in man, human (99–126) ANP 2.0 g·min^–1 was infused IV for 60 min in 8 healthy young (18 to 25 y) and 9 healthy elderly (71 to 84 y) subjects.Both baseline ANP values and the levels at the end of infusion were higher in the elderly subjects. The mean residence time of ANP in the two age groups was not significantly different, whereas total body clearance (CL) was markedly diminished in the elderly as compared to the young subjects (mean±SD 3.1±1.0 l·min^–1 and 6.2±4.1 l·min^–1, respectively). The apparent volume of distribution at steady state was lower in the elderly than in the young, but the difference was not significant (mean±SD 44±19 and 103±111, respectively. The decrease in CL largely explained the higher ANP levels found in the elderly subjects. The MRT and the plasma half-life of the terminal phase did not differ between the two groups.In the elderly but not in the young subjects the calculated endogenous creatinine clearance was closely correlated with the CL (r=0.90, P<0.001), thereby emphasizing the importance of the kidney in the metabolic clearance of ANP in the elderly.     

Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate

Desmethyldiazepam (DMDZ) disposition was evaluated in 32 healthy male and female volunteers who ingested single 15-mg doses of the precursor compound, clorazepate dipotassium. DMDZ concentrations were measured in multiple plasma samples obtained between 7 and 9 days after dosage. Appearance of DMDZ in blood was rapid, with peak concentrations attained on average 1.5 h after dosage. Absorption half-life (t _1/2 a) averaged 24 min. Neither peak time nor t _1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t _1/2 ) of 82 h (range 27–219 h). t _1/2 became prolonged with age in men but not in women Likewise, clearance of total (free plus bound) DMDZ declined with age in male subjects (r=–0.47, P<0.1), but was unrelated to age in women. DMDZ was extensively bound to protein in all subjects. The mean free fraction (FF) was 3.1% (range 2.0–4.3%), and increased significantly with declining plasma albumin concentrations (r=–0.57, P<0.001). Partly due to a decline in plasma albumin with age (r=–0.47, P<0.01), FF tended to increase with age (r=0.23). After correction for individual differences in FF, clearance of pharmacologically active unbound DMDZ declined significantly with age in men (r=–0.62, P<0.01), but actually was slightly higher, in elderly as opposed to young women. Thus, the age-related decline in the capacity for hepatic hydroxylation of DMDZ is highly sex-specific.     

Mianserin protein binding in serum and plasma from healthy subjects and patients with depression and rheumatoid arthritis

Mianserin protein binding was measured in serum from 43 healthy subjects and plasma from 12 elderly depressed patients and 23 patients with rheumatoid arthritis. Free fraction (mean±SD) was 5.5±0.7% in the healthy subjects, 5.0±0.8% in the elderly subjects and 6.0±1.0 in the patients with rheumatoid arthritis. In the group of elderly patients treated with mianserin, a high correlation (r=0.83, P<0.001) between total and free concentrations of mianserin was found. In both groups a high linear correlation (r=+0.90, P<0.001) between the free fraction of mianserin and that of imipramine was found, the latter being about twice as high as for mianserin.In both healthy subjects and arthritis patients the degree of protein binding was positively correlated to the concentration of ₁-acid-glycoprotein and complement C3_c, and somewhat more weakly to haptoglobin. In the healthy subjects protein binding was also highly positively correlated to the concentration of apolipoprotein B, whereas no such correlation was found in the rheumatoid arthritis patients. In the rheumatoid arthritis patients protein binding was highly correlated to the concentration of hemopexin and somewhat more weakly to ceruloplasmin and fibrinogen; a weak negative correlation to the concentration of albumin was also found. Since significant intercorrelations between the concentrations of these proteins were found, the correlation to the degree of binding of mianserin may not necessarily represent binding of the drug to the protein.     

Pharmacokinetics of pirmenol in young and elderly subjects

Summary The steady state pharmacokinetics of pirmenol was compared in twelve healthy young (aged 18 to 45 y) and 11 elderly subjects (over 65 y) subjects given pirmenol HCl 100 mg every 12 h for a total of 14 doses. In addition, the single-dose pharmacokinetics of pirmenol was determined following a 100 mg oral dose in the young subject group for comparison with the results of repeated administration.In the young subjects, the mean single-dose and steady-state CL_R of pirmenol were similar; however, Ae was 29 % higher and CL/f was 22 % lower at steady state than after the single dose. Steady-state (fourteenth dose) C_min, C_max, t_max, z, Ae, CL/f, CL_R and V values were similar in the young and elderly subjects.Based on pharmacokinetic considerations, the dosage of pirmenol is unlikely to differ in young and elderly subjects.     

Absorption and disposition of ampicillin in the elderly

Summary Ampicillin (500 mg) was administered intravenously (i. v.) and orally to a small panel of young and elderly subjects in a cross-over fashion. Plasma concentrations of ampicillin were measured by a fluorimetric technique for 8 h following dosage. A two compartment-open model was used to characterise the plasma concentration-time data for the intravenous study, and a one compartment-open model incorporating an absorption lag time and a first-order absorption rate constant for the oral data. Plasma clearance after i. v. ampicillin was found to be significantly decreased in the elderly (P<0.05, 0.08 1 h^–1kg^–1 versus 0.18 1 h^–1kg^–1), and half life and area under the plasma level-time curve were significantly increased (P<0.05, 6.70 h versus 1.68 h, t_1/2; p<0.01, 176.51 µg·h ml^–1 versus 37.88 µg·h ml^–1, AUC _o ) as compared to the young. No sigificant differences were observed between the age groups for the volume of distribution terms and the changes in drug handling noted in the elderly were attributed to a decrease in the renal elimination of ampicillin. Following oral administration a significant increase in t_1/2, AUC _o and the maximum plasma concentration (C_pmax P<0.01, 6.59 µg ml^–1 versus 3.42 µg ml^–1) of ampicillin was found in the elderly subjects. These findings were similarly attributed to a decrease in drug elimination in the aged, since no apparent age differences were noted in the pharmacokinetic parameters governing both rate and extent of ampicillin absorption.     

Evaluation of pharmacokinetic interaction between cetirizine and ritonavir, an HIV-1 protease inhibitor, in healthy male volunteers

Background Serious adverse effects have been observed with some non-sedative H₁-antihistamines (terfenadine and astemizole) when they were associated with drugs known to inhibit their metabolism. However, this is not a class effect, and this interaction should be considered on a case-by-case basis. The aim of this study was to evaluate the potential of pharmacokinetic interaction between cetirizine and ritonavir, the most potent cytochrome P ₄₅₀ (CYP) inhibitor.Methods An open-label, single-center, one-sequence crossover pharmacokinetic study was conducted in three running periods: cetirizine (CTZ) alone, ritonavir (RTV) alone and then CTZ plus RTV. For each period, steady-state pharmacokinetics were obtained. RTV and CTZ plasma concentrations were determined using validated liquid chromatography methods. The statistical method was based on a 90% confidence interval (CI) for the ratio of population geometric means (combination/drug alone) for each drug and for each parameter [area under the plasma concentration versus time curve (AUC_0-,ss), value of maximum plasma concentration (C_max,ss)] and compared to bioequivalence ranges 80–125% and 70–143% for AUC_0-,ss and C_max,ss, respectively.Results Among the 17 male subjects enrolled (26.4±8.6 years), 16 completed the study (1 withdrawal after the first period). The RTV pharmacokinetic parameter values were not affected by CTZ co-treatment. With RTV, a 42% increase in the CTZ AUC_0-,ss (3406 versus 4840 gh/l, 90% CI of 128–158%), a 53% increase in the CTZ elimination half-life (7.8 h versus 11.9 h, P = 0.001), a slight increase (15%) in the CTZ apparent volume of distribution (V_d,ss/ f) (34.7 l versus 39.8 l, P = 0.035), a 29% decrease in the CTZ apparent total body clearance (49.9 ml/min versus 35.3 ml/min, P<0.001) and bioequivalent C_max,ss (374 g/l versus 408 g/l) were observed. No serious drug related adverse effects were notified.Conclusions CTZ does not significantly affect the pharmacokinetic parameters of RTV, and the association does not, thus, require a modification of the dosage of the protease inhibitor. The increased extent of exposure to CTZ in healthy subjects, in the presence of RTV administered at high doses, remained in the same range as previously observed in the elderly or in mildly renally impaired subjects.Presented in part at the 42nd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, California, 27–30 September 2002, Poster H-1718.     

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.     

A contrast in safety,pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat

AIM

To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women.

METHODS

All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)_1–40 concentratios and exploration of Notch biomarkers.

RESULTS

Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t_max between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ_1–40 serum concentrations showed a pattern of decreasing concentrations over the first 4–6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly.

CONCLUSIONS

The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer''s disease.     

The McCollough effect as a measure of central cholinergic activity in man

The McCollough Effect (ME) is an orientation contingent colour after-effect which has been proposed as an indicator of central neurotransmitter activity. Shute (1979) suggested that the ME could reflect a hippocampal forgetting mechanism which should be inhibited by GABAergic neurones and stimulated by cholinergic neurones. The purpose of the present study was to demonstrate that the ME is in fact sensitive to cholinergic and anticholinergic drugs and to compare its sensitivity to more conventional tests of psychomotor and cognitive function. Ten healthy subjects received single doses of physostigmine (0.75 mg SC), hyoscine (1.2 mg), temazepam (20 mg), flecainide (200 mg) or placebo in a double-blind double-dummy presentation. Subjects were tested on a battery of psychomotor and cognitive function tests at baseline and 1 h, and adapted to the ME at 1.5 h. Visual analogue rating scales and conventional tests of psychomotor function and saccadic eye movements indicated that both subjective and objective measures of arousal were impaired by temazepam. The subjective, but not the objective, measures of arousal were also impaired by both hyoscine and physostigmine, but not by flecainide. Initial strength and duration of the ME were decreased by physostigmine and increased by hyoscine and temazepam, relative to placebo (P<0.01). Thus, the ME is capable of detecting cholinergic, anticholinergic and GABA mimetic drug effects in man, in therapeutic doses.     

Systemic availability of orally administered L-dopa in the elderly Parkinsonian patient

Summary Previous studies have suggested that the absorption of L-dopa in the elderly Parkinsonian patient might be unusually efficient. In the present investigation, the systemic availability of L-dopa was examined in 5 elderly Parkinsonian patients (mean age=77 years) and 6 young, healthy volunteers (mean age=26 years) following a single oral 300 mg dose of L-dopa. Quantitation of plasma levels of intact L-dopa was effected by ion-exchange column chromatography and spectrofluorimetry. The L-dopa plasma concentration-time profiles obtained confirmed the considerable intersubject variability in the absorption of L-dopa previously reported in the literature. Maximum plasma concentrations of L-dopa generally occurred within 60 min of administration of the dose. The existence of more than one plasma peak of L-dopa concentration was displayed in 45% of the subjects studied. This characteristic was not confined exclusively to either subject group. There was a significantly larger (P<0.02) area under the plasma L-dopa concentration-time curve (AUC _o ) in the elderly Parkinsonian patients (mean=234.69 µg · min/ml; SD=84.70) compared to the young, healthy volunteers (mean=82.33 µg · min/ml; SD=31.00). A significant (P<0.01) correlation existed between AUC _o and age (r=0.7970; n=11) among the subjects studied. The apparent elimination phase plasma half-life of L-dopa in the elderly Parkinsonian patients (mean=66.0 min; SD=11.1) was not significantly different to that observed in the young, healthy volunteers (mean=74.0 min; SD=18.1). These results suggest that there may be an age-related alteration to the disposition of orally administered L-dopa in the elderly Parkinsonian patient.     

Effects of carvedilol on serum lipids in hypertensive and normotensive subjects

The effects of carvedilol (an · -blocker) on lipid metabolism were assessed in addition to its hypotensive effect. The subjects were 18 men and 18 women, 20 with hypertension and 16 normotensives with other conditions requiring carvedilol treatment. They were aged from 31 to 79 years and were given a daily dose of 5–20 mg carvedilol (average, 9.7 mg/day) for 12 weeks. Significant falls were seen in blood pressure and heart rate after 12 weeks in the hypertensive subjects (mean ± SE) (systolic: from 164 ± 2 to 141 ± 2 mm Hg,P < 0.001;=" diastolic:=" from=" 98=" ±=" 1=" to=" 85=" ±=" 2=" mm=">P < 0.001;=" heart=" rate:=" from=" 71=" to=" 65=">P < 0.001).=" smaller=" changes=" in=" blood=" pressure=" and=" heart=" rate=" were=" seen=" in=" the=" normotensive=" subjects,=" with=" the=" fall=" in=" systolic=" pressure=" being=" significant=" (from=" 143±3=" to=" 135=" ±=" 2=" mm=">P < 0.01).=" there=" were=" no=" significant=" changes=" in=" the=" overall=" serum=" total=" cholesterol,=" triglycerides,=" high-density=" lipoprotein=" (hdl)=" cholesterol,=" and=" phospholipid=" levels.=" in=" the=" subgroup=" with=" a=" pretreatment=" serum=" triglyceride=" level=" of="> 150 mg/dl, a significant fall of 52.1 mg/dl was seen (P < 0.05).=" lipoprotein=" analysis=" showed=" a=" significant=" fall=" in=">-lipoprotein levels (P < 0.05).=" the=" atherogenic=" index=" did=" not=" change=" significantly,=" and=" it=" was=" concluded=" that=" carvedilol=" was=" an=" effective=" antihypertensive=" agent=" that=" produced=" no=" adverse=" effects=" and=" possibly=" had=" beneficial=" effects=" on=" lipid=">     

Characteristics of plasma protein binding of tacrine hydrochloride: a new drug for Alzheimer's disease

The aim of this study was to characterise the plasma protein binding of tacrine hydrochloride (THA) in vitro. Binding was assessed in the plasma of 11 healthy individuals aged 20 to 27 years using ultrafiltration followed by HPLC assay.At THA concentrations from 10 to 100 ng/ml protein binding ranged from 78.6 to 71.0%. Binding to commercially available human albumin ranged from 41.7 to 38.3% and to human ₁-acid glycoprotein from 23.1 to 12.4% over the THA concentrations from 25 to 100 ng/ml.THA binding and total plasma protein, plasma albumin and ₁-acid glycoprotein were measured in healthy young subjects (n=13), healthy elderly individuals (n=12) and patients hospitalised with acute illnesses (n=8). There were significant differences between the groups in total plasma protein, plasma albumin and in ₁-acid glycoprotein but no differences in the protein binding of THA which remained constant at about 75%. There was no correlation between THA binding and any plasma protein concentration.The THA binding was not high enough to be of major significance clinically or to reduce the validity of total plasma THA measurement in therapeutic monitoring.     

Pethidine binding to blood cells and plasma proteins in old and young subjects

Summary The distribution of³H-pethidine in whole blood was compared in old (63–86 years;n=11) and young (19–25 years,n=12) subjects using equilibrium dialysis. The plasma protein binding was 52.7±3.3% (mean ± SD) in the old subjects and 51.8±3.1% in the young; the difference was not statistically significant. Studies on isolated plasma protein fractions showed that the main pethidine-binding protein was ₁-acid glycoprotein. Accordingly, the degree of pethidine binding is likely to be affected by inflammatory disease rather than by age. The distribution of pethidine to blood cells showed no age-related difference; the ratio between whole blood and plasma concentrations was 0.99 in old and 0.98 in young subjects. In whole blood from old and young subjects, 43% and 41% of pethidine was present in erythrocytes, 27% and 26% in plasma water whereas 30% and 29% was bound to plasma proteins. The mean ratio between pethidine in cells and plasma water (2.01) indicates binding of the drug in or on the blood cells. These in vitro results do not support the previous theory that a decrease in intracellular pethidine distribution in old age was the reason for the reported higher plasma levels. A slower elimination rate remains the most likely explanation for the increased plasma concentration of pethidine in old patients.     

Lack of age and gender effects on single-dose pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem

AIMS

To investigate the effect of age and gender on the tolerability, safety and pharmacokinetics (PK) of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite.

METHODS

Forty-two subjects were assigned to one of the following three groups: young men, elderly men and elderly women. The PK, safety and tolerability of an intravenous infusion of 1500 mg tomopenem and its resultant major metabolite (open beta-lactam ring) were assessed.

RESULTS

Minor differences in exposure of both tomopenem and the major metabolite were seen. The area under the curve (AUC) of tomopenem was 22% higher in elderly men compared with young men, and 19% higher in elderly women relative to the elderly men. Total clearance of tomopenem decreased with decreasing creatinine clearance. In the two male groups, renal clearance values of tomopenem were similar (3.52 and 3.67 l h⁻¹) and higher than in the elderly female group (2.83 l h⁻¹). The mean half-lives ranged from 2.03 (healthy young men) to 2.41 h (elderly men). The difference in AUC of tomopenem can be explained by differences in the mean creatinine clearances of 116 (young men), 101 (elderly men) and 84.7 (elderly women) ml min⁻¹ 1.73 m⁻², respectively.

CONCLUSIONS

While some PK parameters were statistically different among the three groups, the differences were mostly minor and unlikely to be clinically meaningful. The difference in the PK can be largely attributed to the difference in creatinine clearance of these groups.     

Plasma protein binding of risperidone and its distribution in blood

The plasma protein binding of the new antipsychotic risperidone and of its active metabolite 9-hydroxy-risperidone was studied in vitro by equilibrium dialysis. Risperidone was 90.0% bound in human plasma, 88.2% in rat plasma and 91.7% in dog plasma. The protein binding of 9-hydroxy-risperidone was lower and averaged 77.4% in human plasma, 74.7% in rat plasma and 79.7% in dog plasma. In human plasma, the protein binding of risperidone was independent of the drug concentration up to 200 ng/ml. The binding of risperidone increased at higher pH values. Risperidone was bound to both albumin and ₁-acid glycoprotein. The plasma protein binding of risperidone and 9-hydroxy-risperidone in the elderly was not significantly different from that in young subjects. Plasma protein binding differences between patients with hepatic or renal impairment and healthy subjects were either not significant or rather small. The blood to plasma concentration ratio of risperidone averaged 0.67 in man, 0.51 in dogs and 0.78 in rats. Displacement interactions of risperidone and 9-hydroxy-risperidone with other drugs were minimal.     

Comparison of plasma levels of canrenone and metabolites after base hydrolysis in young and elderly subjects following single and multiple doses of spironolactone

Summary Plasma levels of canrenone and total metabolites after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on Day 1, plasma levels of canrenone and total metabolites were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and total metabolites. However, these differences between the two age groups diminished after multiple dosing on Day 8, and the steady state predose plasma levels of canrenone and total metabolites were significantly higher in the elderly subjects. The accumulation ratios of canrenone and total metabolites were significantly higher in the elderly than in the young subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as 1.) a proportionate shift in metabolism with age; 2.) impaired oral absorption of the parent compound; and/or 3.) altered volume of distribution of the drug.     

Plasma level of chlormethiazole and two metabolites after oral administration to young and aged human subjects

Summary The plasma concentration of chlormethiazole and two of its metabolites has been measured in three young and three aged human subjects following administration of a single oral dose of chlormethiazole. A sensitive analytical method based on gas chromatography-mass spectrometry using the selective ion monitoring mode of operation was developed to permit quantitation of the plasma levels. The time course of the plasma concentration of chlormethiazole and metabolites showed wide inter-subject variation, particularly between the young and elderly subjects. Absorption of chlormethiazole was rapid in the subjects of both groups as assessed by the time taken to reach the peak plasma concentration. The mean peak plasma level of chlormethiazole was more than five times greater in the elderly (2.90±1.56 µg/ml) than in the young (0.55±0.58 µg/ml) subjects. The plasma level of chlormethiazole was consistently higher in the aged subjects and this was reflected by the larger area under the plasma curve in aged (7.62±5.37 µg.h/ml) than in young (0.94±0.66 µg.h/ml) individuals. Decreased pre-systemic elimination by the liver has been suggested as an important factor contributing to the higher plasma level in the elderly. Estimates of absolute systemic availability, calculated by reference to previous intravenous studies, were greater for the elderly subjects. The distribution of chlormethiazole in whole blood from six young and six elderly human subjects was investigated in vitro. The unbound fraction of chlormethiazole in plasma increased significantly from 0.308±0.035 in young subjects to 0.403±0.067 in the elderly. Distribution of the drug in whole blood was different for the two age groups; the fraction of drug distributed to plasma water was significantly greater and the fraction in blood cells was significantly less in the aged.     

Additional role of serum 25‐hydroxyvitamin D3 levels in atherosclerosis in Chinese middle‐aged and elderly men

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