Dosage form design for improvement of bioavailability of levodopa IV: Possible causes of low bioavailability of oral levodopa in dogs

Sasahara, Kunihiro; Nitanai, Takashi; Habara, Taeko; Kojima, Tsugio; Kawahara, Yukinori; Morioka, Tadashi; Nakajima, Eiichi

doi:10.1002/jps.2600700705

Cited by 29 publications

(12 citation statements)

References 8 publications

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“…50 to 75% of orally administered levodopa is metabolised by gut decarboxylase before reaching the circulation (Andersson et al 1975;Bergmark et al 1972;Granerus et al 1973). This first-pass effect presumably does not involve the liver, as portal and peripheral vein infusions of levodopa produce identical blood concentrations of the drug (Sasahara et al 1981a). It appears that, at least in rats, transport rather than decarboxylation is rate-limiting (Mearrick et al 1975).…”

Section: Absorption and Distributionmentioning

confidence: 97%

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Cedarbaum

1987

Clinical Pharmacokinetics

172

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Of the neurological disorders, none can claim a battery of therapeutic agents based upon as rational a pharmacology as can Parkinson's disease. In this review, the clinical pharmacokinetics of the major classes of anti-Parkinsonian drugs is discussed. Although they are the oldest drugs in the anti-Parkinsonian armamentarium, little pharmacokinetic data are available regarding the anticholinergic and antihistaminic agents. Based on elimination half-lives of 10 to 18 hours, most could probably be effectively given on a twice-daily schedule. Amantadine is unique among anti-Parkinsonian agents both in lacking a clearly defined mechanism of action and in being eliminated from the body exclusively by renal excretion of unchanged drug. Thus the normal decline of renal function in the elderly Parkinsonian population becomes an important factor in avoiding potential drug toxicity. The pharmacokinetics and pharmacodynamics of levodopa are complex. Since it is an amino acid, it follows metabolic pathways and must compete for absorption and brain uptake with a number of large neutral amino acids. It has a short elimination half-life and, as Parkinson's disease progresses, the brain loses its capacity to store the drug and becomes dependent in a moment-to-moment fashion on plasma levodopa concentrations, creating therapeutic response fluctuations in over 50% of patients. Pharmacokinetic considerations in the management of these response fluctuations are discussed. The newest class of anti-Parkinsonian agents are the direct acting dopamine receptor agonists. These drugs, all derivatives of ergot, have more prolonged durations of anti-Parkinsonian action than levodopa. However, other than bromocriptine, clinical experience with members of this class of drugs is still limited.

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Section: Absorption and Distributionmentioning

confidence: 97%

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Cedarbaum

1987

Clinical Pharmacokinetics

172

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“…The effect reflect a poor response to levodopa therapy [19,37]. With ascending benserazide dose, the 3-OMD/levodopa AUC containing abundant decarboxylase activity [38,39]. Levodopa and DOPAC had very similar half-lives which ratio increased (Figure 4), thus providing a rationale for triple therapy with levodopa, and inhibitors of both could indicate that decarboxylation rather than deamination is the rate-limiting step in the formation of DOPAC.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*

Dingemanse¹,

Kleinbloesem²,

Zürcher

et al. 1997

Brit J Clinical Pharma

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Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple‐dose regimens. Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3‐O‐methyldopa (3‐OMD) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa. Results Endogenous concentrations of levodopa and 3‐OMD increased dose‐dependently (from 8 up to 52 μg l−1 and from 0.02 up to 0.50 mg l−1, respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration‐time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l−1 h at benserazide doses of 100–200 mg three times daily. Benserazide caused a dose‐dependent increase in the AUC of 3‐OMD from 7.4 to 106 mg l−1 h at doses of 200 mg. Formation of DOPAC was dose‐dependently suppressed, with benserazide 5 mg three times daily already halving its AUC. Conclusions The benserazide‐dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.

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“…Comparison of the AUC of levodopa following oral, peripheral intravenous and rapid portal vein administration to dogs indicated that the intestinal wall was the major site of first pass metabolism (Sasahara et al, 1981). Furthermore, a study of levodopa decarboxylation using an in situ rat jejunal preparation provided evidence that the gut rather than the liver was the major site of first pass metabolism (Iwamoto et al, 1987).…”

Section: Study B Levodopa Plus Carbidopamentioning

confidence: 99%

The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa.

Robertson

Wood

Everest

et al. 1989

Brit J Clinical Pharma

105

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1. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa was investigated in young and elderly healthy volunteers. 2. The plasma clearance of levodopa following intravenous administration of 50 mg was 14.2 +/‐ 2.8 (s.d.) ml min‐1 kg‐1 in the elderly compared with 23.4 +/‐ 4.1 ml min‐1 kg‐1 in the young (P less than 0.01) which resulted in a 49% greater area under the plasma concentration‐time curve (AUC) in the older subjects (P less than 0.01). The volume of distribution (Vss) was lower in the elderly (1.01 +/‐ 0.29 l kg‐1) than in the young (1.65 +/‐ 0.39 l kg‐1) (P less than 0.002). 3. Following oral administration of 250 mg of levodopa the AUC was 2512 +/‐ 588 ng ml‐1h in the elderly compared with 1056 +/‐ 282 ng ml‐1h in the young (P less than 0.002). Cmax was also significantly greater in the elderly (P less than 0.05). The bioavailability of levodopa was significantly greater in the elderly (0.63 +/‐ 0.12 compared with 0.41 +/‐ 0.16, P less than 0.01). 4. In the presence of carbidopa, the plasma clearance of intravenous levodopa (50 mg) was reduced in both age groups but remained lower in the elderly (5.8 +/‐ 0.9 ml min‐1 kg‐1 compared with 9.3 +/‐ 1.0 ml min‐1 kg‐1; P less than 0.01). This resulted in a 54% greater AUC in the older subjects (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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Dosage form design for improvement of bioavailability of levodopa IV: Possible causes of low bioavailability of oral levodopa in dogs

Cited by 29 publications

References 8 publications

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*

The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa.

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