Dose-dependent Pharmacokinetics of Laevodopa and its Metabolites in the Rat

Cheng, Lawrence K.; Fung, Ho‐Leung

doi:10.3109/00498257609151633

Cited by 3 publications

(3 citation statements)

References 14 publications

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“…The dose-dependency of L-dopa and dopamine appearances in the vascular perfusate is consistent with the kinetics observed in-vivo after oral administration of L-dopa to rat (Cheng & Fung 1976), dog and man (Sasahara et all980). In these experiments the area under the plasma concentration time curves (AUC) for L-dopa was found to increase nonlinearly with the dose.…”

Section: Discussionsupporting

confidence: 86%

“…In the rat the contribution of the gut wall to the overall first-pass effect of L-dopa appeared to be greater than that of the liver (Iwamoto et a1 1987). Following oral administration of L-dopa to man, dog (Sasahara et al 1980) and rat (Cheng & Fung 1976) dosedependent pharmacokinetics were observed. In addition, competition for absorption by other amino acids may occur.…”

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confidence: 99%

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Decarboxylation of l-Dopa in the Rat Isolated Vascularly Perfused Small Intestine: Contribution to Systemic Elimination and Dose-dependent First Pass Effect

Vries

Hamelijnck

Hofman

et al. 1992

Journal of Pharmacy and Pharmacology

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The contribution of the rat small intestine to systemic and presystemic elimination of L-dopa was studied. When L-dopa was administered into the vascular perfusate, a systemic extraction ratio of 0.38 was found, the major part being decarboxylated to dopamine. The intestinal L-dopa clearance was estimated to be 17.1 mL min-1 kg-1. Thus, L-dopa intestinal clearance in rat represents up to at least 20% of the total body clearance. After luminal administration of L-dopa 83-88% of the administered dose was absorbed within 60 min. The total amount of L-dopa appearing in the vascular perfusate increased more than proportionally to the increase in the dose. In contrast, the amount of dopamine increased less than proportionally to the dose. As a result, the intestinal first pass appeared to be strongly dose-dependent. Since the total percentage absorbed from the lumen was independent of the administered dose and the total amount that appeared in the vascular perfusate increased linearly with the dose, the dose dependency was probably due to saturation of intestinal L-dopa decarboxylation.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Decarboxylation of l-Dopa in the Rat Isolated Vascularly Perfused Small Intestine: Contribution to Systemic Elimination and Dose-dependent First Pass Effect

Vries

Hamelijnck

Hofman

et al. 1992

Journal of Pharmacy and Pharmacology

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“…High oral doses of levodopa appear to be necessary to saturate gastro-intestinal oral levodopa dosage, the bio-availability of levodopa in the plasma, as indicated by plasma time-concentration curves, shows an exponential rise. (16).…”

Section: Levodopa Absorptionmentioning

confidence: 99%

Variability in Parkinson's disease; clinical aspects, causes and treatment

Parkes¹

1983

Acta Neurologica Scandinavica

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As we have earlier shown, sudden extreme changes in disease severity are a characteristic feature of Parkinson's disease. These variations take two main .forms, those natural to the disease and those occurring as a result of treatment. Treatment-related response variations can sometimes be attributed to the known pharmacokinetic properties of anti-parkinsonian drugs and, in particular, levodopa. These responses are time-dependent. In contrast, other types of response variation may be unpredictable in time, and are at present rarely amenable to treatment. Identification of the cause of variation is necessary for the management of parkinsonism, and particularly for the successful use of deprenyl.

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Peripheral Pharmacokinetic Handling and Metabolism of L-Dopa in the Rat: The Effect of Route of Administration and Carbidopa Pretreatment

Rose

Jenner

Marsden

1991

Journal of Pharmacy and Pharmacology

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The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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Dose-dependent Pharmacokinetics of Laevodopa and its Metabolites in the Rat

Cited by 3 publications

References 14 publications

Decarboxylation of l-Dopa in the Rat Isolated Vascularly Perfused Small Intestine: Contribution to Systemic Elimination and Dose-dependent First Pass Effect

Decarboxylation of l-Dopa in the Rat Isolated Vascularly Perfused Small Intestine: Contribution to Systemic Elimination and Dose-dependent First Pass Effect

Variability in Parkinson's disease; clinical aspects, causes and treatment

Peripheral Pharmacokinetic Handling and Metabolism of L-Dopa in the Rat: The Effect of Route of Administration and Carbidopa Pretreatment

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