Relationship between Dose and Plateau Levels of Drugs Eliminated by Parallel First-Order and Capacity-Limited Kinetics

Tsuchiya, Tamehiro; Levy, Gerhard

doi:10.1002/jps.2600610409

Cited by 61 publications

(8 citation statements)

References 6 publications

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“…The steady-state concentration-dose relationship observed for paroxetine suggests that in most patients paroxetine is eliminated in parallel by a high-affinity saturable process and a linear process. 22 Because of the fact that steady-state plasma concentrations on five to seven different dose levels were obtained in the extensive metabolizers, we were able to show that this VOLUME 51 NUMBER 3…”

Section: Discussionmentioning

confidence: 85%

Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: Nonlinearity and relation to the sparteine oxidation polymorphism

Sindrup

Brøsen

Gram

1992

Clin Pharmacol Ther

145

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Steady-state plasma concentrations of paroxetine were studied at five or more paroxetine dose levels (10 to 70 mg/day) in each of 13 extensive metabolizers of sparteine and at three or four dose levels (10 to 40 mg/day) in each of three poor metabolizers of sparteine, all treated for diabetic neuropathy symptoms. On a dose of 30 mg/day there was a 25-fold variation in steady-state concentrations (25 to 670 nmol/L). The upper extreme of this variation was made up by the poor metabolizers of sparteine and the lower extreme by some fast extensive metabolizers. Further, within the extensive metabolizer group, steady-state levels showed a significant, positive correlation with sparteine metabolic ratio at all dose levels. On increasing doses, a disproportionate increase in plasma drug levels was observed in the majority of patients. In nearly all extensive metabolizers the concentration-dose data were best described by a pharmacokinetic model assuming elimination by at least two kinetically distinct processes, one a high-affinity saturable process and one a low-affinity linear process. Estimates of clearance at low drug levels of the high-affinity process showed a significant negative correlation with the sparteine metabolic ratio. Clearance of the low-affinity process was not related to the metabolic ratio and was of the same magnitude in extensive and poor metabolizers. The data thus confirmed that the metabolism of paroxetine and sparteine cosegregates and indicated that the enzyme responsible for a high-affinity saturable paroxetine elimination process is identical with CYP2D6, the source of the sparteine oxidation polymorphism.

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Section: Discussionmentioning

confidence: 85%

Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: Nonlinearity and relation to the sparteine oxidation polymorphism

Sindrup

Brøsen

Gram

1992

Clin Pharmacol Ther

145

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“…For drugs which are eliminated by first order kinetics after repeated dosing, the drug attains a plateau level, which is proportional to the dose administered, but when drugs are eliminated by non-linear kinetics the magnitude of the plateau is not directly proportional to the dose but may change in a manner other than proportionately (Tsuchiya & Levy, 1972). The results presented here indicate that neostigmine is eliminated by non-linear mechanisms after portal vein administration (which is equivalent to the route used for therapy).…”

Section: Discussionmentioning

confidence: 99%

The Pharmacokinetics of Neostigmine and 3‐hydroxyphenyltrimethylammonium in the Rat: Dose‐dependent Effects After Portal Vein Administration

Barber

Bourne

1974

British J Pharmacology

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The elimination kinetics of [14C]‐neostigmine iodide and [14C]‐3‐hydroxyphenyltrimethylammonium iodide (3‐OH PTMA) have been studied in the rat. The presence of a renal secretory pathway for neostigmine and 3‐OH PTMA has been confirmed. For neostigmine and 3‐OH PTMA, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that both compounds are subject to extensive metabolism during the first passage through the liver. Neostigmine was eliminated by dose‐independent kinetics after jugular vein administration but dose‐dependent after portal vein administration. In the latter case the fraction eliminated as neostigmine increased with increasing dose. This increase was not accompanied by any change in the fraction of the metabolites eliminated. After portal vein administration of 3‐OH PTMA, the fraction of the dose eliminated as 3‐OH PTMA also increased with increasing dose. This change was accompanied by a decrease in the fraction of the metabolites eliminated which were excreted at a constant rate.

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“…Salicylates are much more difficult to use to control inflammation in elderly patients because tinnitus, which can be used as a guide to therapeutic salicylate concentrations in younger patients, often does not occur in patients with underlying hearing loss 23 . The capricious pharmacokinetics of salicylates, whereby the plasma half‐life increases in parallel to the plasma concentration, creates the potential for serious toxicity with increments in dosage of even only one tablet 24 . This phenomenon is especially hazardous in the elderly.…”

Section: Nonsteroidal Anti‐inflammatory Agents (Nsaids)mentioning

confidence: 99%

Problems of Antiarthritic Therapy in the Elderly

Brooks

Kean

Kassam

et al. 1984

J American Geriatrics Society

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Rheumatic diseases are prevalent in the elderly population, resulting in high morbidity caused mainly by lack of mobility. Consequently, the use of antirheumatic drugs in older persons is extensive. This review outlines some of the hazards encountered in the use of antirheumatic drugs in the elderly. Analgesics such as propoxyphene and acetaminophen are useful adjuncts to the treatment of arthritic pain, but propoxyphene has been associated with respiratory depression, and renal clearance of acetaminophen is reduced in elderly subjects. Salicylates may cause deafness, and like the other nonsteroidal anti-inflammatory drugs, may cause salt and water retention resulting in congestive cardiac failure. Phenylbutazone should not be used because of the risk of blood dyscrasia, and indomethacin has been reported as interfering with the antihypertensive effect of beta-blockers. Chloroquine levels may be raised in patients with impaired renal function, and there is increased risk of retinal damage with the drug in elderly subjects. Injectable gold compounds and penicillamine are not contraindicated in the elderly, because they are just as efficacious as in younger persons for the treatment of rheumatoid arthritis. Toxicity due to gold compound is not increased in the elderly, but skin rashes and abnormalities of taste do occur more commonly in elderly patients treated with penicillamine. Corticosteroids do not affect disease progression and therefore should be used only in acute severe disease for short periods of time. As in the younger population, treatment of gout in the elderly is dependent on renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

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Relationship between Dose and Plateau Levels of Drugs Eliminated by Parallel First-Order and Capacity-Limited Kinetics

Cited by 61 publications

References 6 publications

Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: Nonlinearity and relation to the sparteine oxidation polymorphism

Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: Nonlinearity and relation to the sparteine oxidation polymorphism

The Pharmacokinetics of Neostigmine and 3‐hydroxyphenyltrimethylammonium in the Rat: Dose‐dependent Effects After Portal Vein Administration

Problems of Antiarthritic Therapy in the Elderly

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