To determine whether the oscillating clinical response to levodopa in Parkinson's disease (the "on-off" phenomenon) reflects fluctuations in absorption and transport of the drug, we investigated this phenomenon in nine patients with an oscillating motor state. We studied the response to continuous infusion of levodopa and the effects of meals on the plasma levodopa concentrations and on the clinical response during oral and intravenous administration of the drug. Meals reduced peak plasma levodopa concentrations by 29 per cent and delayed absorption by 34 minutes. Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 hours in all of six patients and for up to 36 hours in some. High-protein meals or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body weight) reversed the therapeutic effect of infused levodopa without reducing plasma levodopa concentrations. Glycine and lysine at identical doses had no effect. We conclude that interference with absorption of levodopa by food and by competition between large neutral amino acids and levodopa for transport from plasma to the brain may be partly responsible for the fluctuating clinical response in patients with Parkinson's disease.

The pharmacokinetics of short and long intravenous infusions of levodopa with and without concurrent oral administration of carbidopa was studied in 9 parkinsonian patients. Carbidopa reduced by 50% both the infusion rate required to produce a clinical response and the time required for plasma clearance of levodopa. Using this value for clearance, it is estimated that carbidopa doubles the bioavailability of orally administered levodopa. Carbidopa did not alter the therapeutically effective plasma concentration of levodopa, suggesting that carbidopa does not modify the so-called enzymatic blood-brain barrier. The decline of the plasma levodopa concentration was biphasic; carbidopa modestly increased half-lives of both phases. The apparent volume of distribution was not significantly altered. Carbidopa did not change the duration of the clinical response after the discontinuation of short infusions. From these observations we infer that the therapeutic effects of carbidopa can be attributed to doubling the bioavailability of orally administered levodopa and halving its plasma clearance.

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The renal handling of vancomycin is unknown. Previously reported studies have not achieved steady-state conditions with constant vancomycin concentrations. We measured systemic vancomycin clearance simultaneously with the renal clearances of vancomycin, creatinine, inulin, and para-aminohippurate in nine healthy subjects at steady-state serum vancomycin concentrations of 7 and 14 mg/L. For all steady-state observations the renal clearance of vancomycin was 89 +/- 11 ml/min (mean +/- SE), the clearance of inulin 105 +/- 9 ml/min, the clearance of creatinine 117 +/- 9 ml/min, and the clearance of para-aminohippuric acid 496 +/- 41 ml/min. The systemic clearance of vancomycin was 131 +/- 7 ml/min. The clearances of creatinine, inulin, and para-aminohippuric acid and the renal clearance of vancomycin were not statistically different at both steady-state vancomycin concentrations. The ratio of the renal clearance of vancomycin to the clearance of inulin was 0.89 +/- 0.06 and to creatinine clearance 0.79 +/- 0.05. Both ratios were independent of vancomycin concentration, urine flow rate, and filtration fraction. The systemic clearance of vancomycin was 10% greater at serum vancomycin concentrations of 14 mg/L than at 7 mg/L (p less than 0.05) because of an increase in the nonrenal clearance. Therefore in healthy subjects, 30% of the systemic vancomycin clearance is by nonrenal mechanisms and this nonrenal clearance is concentration dependent. Assuming protein binding to be between 10% and 20%, renal vancomycin excretion is predominantly by glomerular filtration. Small amounts of tubular vancomycin transport cannot be excluded by these techniques.