Changes in drug metabolism with increasing age: 2. phenytoin clearance and protein binding.

110

1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half‐lives averaged 9.0 +/− 1.4 h (s.d.). Volumes of distribution were 0.175 +/− 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half‐lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5–2 h. Biological availability was 96 +/− 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.

Section: Discussionmentioning

confidence: 91%

Disposition of sodium valproate in epileptic patients.

Perucca¹,

Gatti²,

Frigo³

et al. 1978

110

“…However, the change in the volume of distribution and slightly higher clearance may reflect alterations in protein binding. It has been shown that plasma concentrations of albumin decrease with age (Woodford-Williams et al, 1964) leading to changes in free drug fraction and consequently to changes in clearance and volume of distribution (Greenblatt et al, 1980 (Triggs & Nation, 1975;Hayes et al, 1975;Bach et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetics of doxazosin in elderly normotensives.

Vincent¹,

Modesti²,

Elliott³

et al. 1986

The pharmacokinetics of doxazosin were studied in 12 normotensive elderly volunteers aged 62-89 years. There was marked inter-individual variability in all the parameters derived but the disposition of doxazosin was similar in both sexes. These results were compared to those of a group of young normotensive volunteers aged 23-39 years studied previously under comparable conditions. The volume of distribution increased significantly with age although the bioavailability and clearance were not significantly different in the two groups. These results suggest that age is unlikely to influence the disposition of doxazosin to a clinically significant extent.

“…Pharmacokinetic studies in the elderly have been performed using intravenous administration with only a few drugs including antipyrine (O'Malley etal., 1971) phenytoin (Hayes, Langman & Short, 1975) diazepam (Klotz et al, 1975), chlordiazepoxide (Roberts et al, 1978), propranolol (Castleden & George, 1979), chlormethiazole and lignocaine (Triggs, 1979).…”

Section: Discussionmentioning

confidence: 99%

Prazosin disposition in young and elderly subjects.

Rubin¹,

Scott²,

Reid³

1981

1 The disposition of prazosin following oral and intravenous administration has been studied in seven young and seven elderly men, all of whom were in good health and living independently in the community. 2 The elimination half-life (min) of prazosin was 123 + 19.4 (s.d.) in the young and 194 + 36 in the elderly (P < 0.01). 3 Clearance (ml min-m kg-') was 3.94 + 0.73 in the young and 3.53 + 1 in the elderly (P > 0.1). Volume of distribution at steady state (1 kg-') was 0.63 + 0.14 in the young and 0.89 + 0.26 in the elderly (P < 0.05). 4 The absolute bioavailability of orally administered prazosin was 0.68 -+ 0.17 in the young and 0.48 + 0.16 in the elderly (P < 0.05). 5 The significant increase in prazosin half-life in the elderly results from an increased volume of distribution, not from decreased clearance. 6 Gastrointestinal absorption of prazosin decreases in old age.