Gastrointestinal,liver, and lung extraction ratio of acetaminophen in the rat after high dose administration

The pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg^?1 by the intra-arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen-glucuronide and acetaminophen-sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first-pass effect after oral absorption) was determined. A mean oral extraction ratio of 0·49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0·52, 0·07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first-pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first-pass effect of acetaminophen may be dose-dependent.     

Resistance of the guinea pig to indomethacin ulcerogenesis

Steroid or nonsteroid anti-inflammatory drugs are said to induce gastrointestinal lesions in laboratory animals and man. Oral or parenteral administration of indomethacin (12 mg/kg) produced a 100% incidence of intestinal ulcerations, peritonitis, and death in the rat. In contrast, indomethacin failed to induce any intestinal or gastric ulceration in the guinea pig after a single intravenous dose (25–50 mg/kg) or prolonged oral administration (50, 100, and 150 mg/kg/day for 15 days). The results show a clear-cut species difference for the toxic effects of indomethacin and cortisone. The relationship, if any, between ulcerogenic sensitivity and the inhibition of indomethacin and cortisone of prostaglandin biosynthesis or release is not known.     

Griseofulvin---phenobarbital interaction: a formulation-dependent phenomenon

The reported interaction of griseofulvin with phenobarbital was studied in the rat following oral administration of different dosage forms. A single oral dose of 15 mg of phenobarbital/kg 24 hr prior to the oral administration of a suspension of 100 mg og griseofulvin/kg in 0.5% polysorbate 80 significantly reduced plasma griseofulvin levels. An increase in the concentration of polysorbate 80 to 2% reduced the extent of the interaction from 50 to 32%. Phenobarbital did not influence plasma griseofulvin levels when griseofulvin was given in either 70% polyethylene glycol 300 (suspensions of 20 or 100 mg/kg) or 100% polyethylene glycol 600 (solution of 50 mg/kg). It is concluded that the observed interaction is formulation dependent and is a result of diminished dissolution and, consequently, reduced absorption of griseofulvin.     

Pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats

This study reports the absorption, dose-linearity and pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats after i.v. and oral administration at doses of 5, 10 and 25 mg/kg on both occasions. Concentrations of KR-31831 were determined by a validated LC/MS/MS assay method. After i.v. injection, plasma concentration-time profiles showed multi-compartmental characteristics, and there were no significant differences in Cl (20.8-27.7 ml/min/kg) and dose-normalized AUC (178.1-231 microg x min/ml based on the 5 mg/kg dose) as a function of dose. However, Vss was significantly increased at the 25 mg/kg dose (4931 ml/kg) compared with those (2288-2421 ml/kg) at lower doses. Subsequently, t1/2 was increased from 143-159 min at the lower doses to 304 min at the 25 mg/kg dose. The altered VSS was found to be a result of reduced plasma protein binding at relatively high concentrations. Following oral administration (doses 5-25 mg/kg), the absolute oral bioavailability ranged from 37.8% to 46.3%, and there were no significant alterations in dose-normalized AUC, Tmax, Cmax and t1/2 as a function of dose. The extent of urinary excretion was low for both i.v. (0.35%-0.54%) and oral (0.13%-0.33%) doses. Further discussions on the chemical and microsomal stability were included. In conclusion, dose-independent absorption kinetics were observed at oral doses from 5 to 25 mg/kg in rats. Orally administered KR-31831 could be eliminated mainly by the liver metabolic pathway.     

Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats.

The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.     

Pharmacokinetics of (−)-epicatechin in rabbits

The aim of this study was to investigate the pharmacokinetics of (−)-epicatechin (EC) in rabbits after intravenous, intraperitoneal, and oral administration. A two-compartment model was used to describe the pharmacokinetics of EC after intravenous administration. EC showed dose-independent pharmacokinetics after intravenous administration. In addition, the area under the concentration-time curve was proportional to the dose over the range 5–25 mg/kg. After intraperitoneal administration of 25 mg/kg, a high percentage of EC escaped from first-pass hepatic elimination. After oral administration of 50 mg/kg, there was a great variation in the pharmacokinetics, and the mean oral bioavailability of EC was 4%. There was no significant difference in the elimination rate constants in all treatments (p>0.05). In conclusion, after intravenous, intraperitoneal, and oral administration of EC, the EC exhibits dose-independent pharmacokinetics in rabbits. The first-pass effect did not participate in the low oral bioavailability. Base on the results of the present study, the other factors may contribute the low oral bioavailability.     

Dose-independent pharmacokinetics of a new reversible proton pump inhibitor,KR-60436, after intravenous and oral administration to rats: gastrointestinal first-pass effect

Dose-independent pharmacokinetic parameters of KR-60436, a new proton pump inhibitor, were evaluated after intravenous (i.v.; 5, 10, and 20 mg/kg) and oral (20, 50, and 100 mg/kg) administration to rats. The hepatic, gastric, and intestinal first-pass effects were also measured after iv, intraportal (i.p.), intragastric (i.g.), and intraduodenal (id) administrations to rats of a dose of 20 mg/kg. The areas under the plasma concentration-time curve from time to zero to time infinity (AUCs) were independent of iv and oral dose ranges studied; the dose-normalized AUCs were 83.0-104 microg. min/mL (based on 5 mg/kg) and 78.4-96.8 microg. min/mL (based on 20 mg/kg) for iv and oral administration, respectively. After an oral administration at a dose of 20 mg/kg, approximately 3% of the oral dose was not absorbed, and the extent of absolute oral bioavaliability (F) was estimated to be 18.8%. The AUCs of KR-60436 after i.g. and i.d. administration at a dose of 20 mg/kg were significantly smaller (82.4 and 57.5% decrease, respectively) than that after an i.p. administration at a dose of 20 mg/kg, suggesting that gastrointestinal first-pass effect of KR-60436 was approximately 80% of oral dose in rats (the gastric first-pass effect was approximately 25%). After an i.p. administration at a dose of 20 mg/kg, the AUC was 77.6% of an iv administration, suggesting that hepatic first-pass effect was approximately 22% of KR-60436 absorbed into the portal vein. Note that the value of 22% was equivalent to approximately 4% of the oral dose. Because only 17% of oral dose was absorbed into the portal vein, the low F of KR-60436 in rats was mainly due to considerable gastrointestinal first-pass effect, which was approximately 80% (the gastric first-pass effect was approximately 25%) of oral dose.     

Dose‐dependent pharmacokinetics and first‐pass effects of mirodenafil,a new erectogenic,in rats

The pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, after intravenous (5, 10, 20 and 50 mg/kg) and oral (10, 20 and 50 mg/kg) administration of mirodenafil, and the first‐pass effect of mirodenafil after intravenous, oral, intraportal, intragastric and intraduodenal (20 mg/kg) administration of mirodenafil were evaluated in rats. The pharmacokinetics of mirodenafil and SK3541 were dose‐dependent after both intravenous and oral administration of mirodenafil due to the saturable hepatic metabolism of mirodenafil. After oral administration of mirodenafil, approximately 2.59% of the oral dose was not absorbed, the F value was approximately 29.4%, and the hepatic and gastrointestinal first‐pass effects of mirodenafil were approximately 21.4% and 54.3% of the oral dose, respectively. The low F value of mirodenafil in rats was mainly due to considerable hepatic and gastrointestinal first‐pass effects in rats. The equilibrium plasma‐to‐blood cell partition ratios of mirodenafil were independent of the initial blood mirodenafil concentrations of 1–10 µg/ml; the mean values were 1.08–1.21. The plasma binding values of mirodenafil to rat plasma was 87.8%. Copyright © 2009 John Wiley & Sons, Ltd.     

Effects of chlorpromazine and atropine on acetaminophen absorption in rabbits

The effects of chlorpromazine and atropine on the gastrointestinal absorption of acetaminophen were investigated in rabbits. Two doses of chlorpromazine and atropine were injected intraperitoneally 30 min prior to the oral administration of acetaminophen. Blood samples were collected before and 0.25,0.5,0.75, 1.0,1.5,2,3,4,5 and 6 h after acetaminophen administration and were analyzed for acetaminophen contents using a HPLC method. Chlorpromazine at a 10 mg/kg dose significantly reduced the maximum plasma concentration (C_max) of acetaminophen from 64.2 ± 2.8 to 40.0 ± 6.3 μgg/ml(P < 0.05). In addition, chlorpromazine at 5 and 10 mg/kg doses significantly increased the time taken to reach the maximum plasma concentration (T_max) of acetaminophen from 0.29 ± 0.04 to 0.67 ± 0.15 and 0.96 ± 0.21h, respectively (P < 0.05). Atropine at 0.5 and 1.0 mg/kg doses also significantly reduced the C_max of acetaminophen from 69.6 ± 4.7 to 45.6 ± 3.7 and 45.9 ± 6.7 μg/ml, respectively (P < 0.05). However, atropine has little effect on T_max of acetaminophen. Both chlorpromazine and atropine did not seem to affect the area under the plasma concentration-time curve and the elimination half-life of acetaminophen. It was concluded that chlorpromazine and atropine affect the rate but not the extent of acetaminophen absorption, by delaying the gastric emptying.     

Dose-dependent pharmacokinetics of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage in dogs

Dose-dependent pharmacokinetic parameters of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage, were evaluated after intravenous and oral administration of the drug at doses of 5, 10 and 25 mg/kg to male beagle dogs. After intravenous administration, the dose-normalized (based on 5 mg/kg) areas under the plasma concentration-time curve from time zero to time infinity (AUC values, 725, 1450 and 2300 micro g min/ml for 5, 10 and 25 mg/kg, respectively) were significantly different among the three dose ranges studied; the value increased more proportionally as the dose increased. This could be due to slower total body clearance (Cl) with increasing doses (6.90, 3.46 and 2.17 ml/min/kg). The slower Cl value with increasing doses may be due to saturable metabolism of KR-31378 in dogs. After oral administration, the dose-normalized (based on 5 mg/kg) AUC values (833, 1450 and 1920 micro g min/ml) at 5 mg/kg were significantly smaller than those at 10 and 25 mg/kg. Note that the AUC values were comparable (not significantly different) between intravenous and oral administration at all doses studied, indicating that the absorption of KR-31378 from the gastrointestinal tract was essentially complete and the first-pass (gastric, intestinal and/or hepatic first-pass) effects were almost negligible in dogs.     

Pharmacokinetics of lithospermic acid B isolated from Salvia miltiorrhiza in rats

The absorption and pharmacokinetics of an active component of Salvia miltiorrhiza, lithospermic acid B (LSB), was investigated after intravenous and oral administration of doses of 10 or 50 mg LSB/kg to rats. Concentrations of LSB were determined by a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay method. After intravenous administration of 50 mg/kg, dose-normalized (10 mg/kg) area under the curve (AUC) (993 microg.min/ml) was significantly greater than that at 10 mg/kg (702 microg.min/ml). The slower clearance Cl-at 50 mg/kg could be due to saturable metabolism of LSB in rats, and this could be supported by significantly slower Cl(NR) and significantly greater 24-h urinary excretion of LSB at 50 mg/kg than at 10 mg/kg. Following oral administration of LSB, the extent of LSB recovered from the entire gastrointestinal tract at 24 h ranged from 41.2% to 23.3%. Although LSB was not detected (limit of quantitation 10 ng/ml) in plasma after oral dose of 10 mg/kg, the absolute oral bioavailability at 50 mg/kg was 5%. Since LSB was shown to have low permeability through the Caco-2 cell monolayers, the low bioavailability of LSB could be due to poor absorption and metabolism.     

Characterization of intestinal absorption of quinidine, a P-glycoprotein substrate, given as a powder in rats

The characteristics of intestinal absorption of quinidine, a P-glycoprotein (P-gp) substrate in biopharmaceutics classification system (BCS) Class I, after oral administration as a powder in No. 9 HPMC capsule (diameter 2.6 mm; length 8.4 mm, volume 25 microl) was examined in rats from the following viewpoints: (i) main absorption site of quinidine, (ii) effect of dosage amounts (or luminal concentrations) of quinidine (10 mg vs 0.1 mg/kg), (iii) contribution of P-gp in quinidine absorption (0.1 mg/kg), and (iv) effect of gastric pH on quinidine absorption. Quinidine administered orally at a dose of 10 mg/kg was discharged from the stomach steadily with time and disappeared rapidly from the proximal intestine, where P-gp expression was low. In contrast, quinidine administered at a dose of 0.1 mg/kg remained longer in the gastrointestinal lumen than that administered at a dose of 10 mg/kg. The pretreatment with cyclosporine A, a P-gp inhibitor, greatly increased the intestinal absorption of quinidine given at a dose of 0.1 mg/kg. The gastric pH in untreated control rats was pH 3.6, and the treatment with ranitidine (10mg/kg, ip), a H2 blocker, increased to pH 6.4. The recovered amounts of quinidine 30 min after administration were 21.1% of dose in control rats and 94.7% in ranitidine-treated rats. The value of plasma AUC(0-6h) of quinidine in ranitidine-treated rats was about 40% that in untreated control rats. In conclusion, quinidine was rapidly and efficiently absorbed at the proximal intestine under ordinary circumstances. However, the oral bioavailability was modulated by various factors including the dose (or luminal concentration at the absorption site), presence of P-gp inhibitors, and gastrointestinal pH.     

Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats

The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance.     

Absorption, protein binding, pharmacokinetics and excretion of the anti-ischemic and anti-hypertensive arylpiperazine derivative CDRI-93/478 in rats

CDRI-93/478 (1- [4-(4-fluorophenyl) piperazine-1-yl]-3-(2-oxopyrrolidin-1-yl) propane hydrochloride, an arylpiperazine derivative, is a potent anti-ischemic and anti-hypertensive agent and is in advanced stage of preclinical trials. In order to develop CDRI-93/478 into a clinical agent, the absorption, protein binding, pharmacokinetics, and excretion of the compound were investigated in male Sprague-Dawley rats. Oral absorption was evaluated in situ and in vivo, using the portal-venous concentration difference method. The compound showed negligible absorption (ka = 0.01 h(-1)) at pH 2.6. However, the rate of absorption of the compound at pH 7.4 was 0.6 h(-1) and was comparable to that observed in the in vivo study (ka, >0.58 h(-1)) in rats after a single 2 mg/kg oral dose. In vitro and in vivo protein binding studies using the ultrafiltration method showed that the compound was subject to low protein binding (<40%) and was independent of the substrate concentration over a range of 1-16 microg/ml. Pharmacokinetic parameters of the compound were determined after intravenous and oral administration of 0.6, 2 and 8 mg/kg doses using a model independent method. After oral administration, the compound showed the double-peak phenomenon, which could be due to the high water solubility (log P, 1.01 +/- 0.01), regional differences in the gastrointestinal absorption and enterohepatic recirculation effects. The absorption of CDRI-93/478 was rapid and showed a bioavailability of 69.9 +/- 5.1% (mean +/- S. D.) after 2 and 8 mg/kg oral dose. However, the pharmacokinetic parameters of the compound could not be determined after the 0.6 mg/kg oral dose due to insufficient data points. The studies following intravenous and oral administration demonstrated linear pharmacokinetics, low clearance and high volume of distribution over the dose range studied. The excretion studies after the 8 mg/kg oral dose indicated that the compound was not excreted through the feces and the urinary excretion was very low (<2%).     

Effects of concomitant aspirin administration on the pharmacokinetics of indomethacin in man

Ten healthy volunteers each received single and multiple 50-mg doses of indomethacin orally and a single 25-mg dose of [ ¹⁴ C]indomethacin intravenously in the absence of and concomitantly with 1200 mg of aspirin as a single dose and in a chronic t.i.d. regimen. Systematic analysis of the data resulted in the isolation and quantification of aspirin's effects on the absorption, distribution, biotransformation, excretion, enterohepatic circulation, and accumulation of indomethacin. The effects of chronic aspirin were to suppress the renal clearance, to increase the biliary clearance, to decrease the efficiency of gastrointestinal absorption, and to enhance the enterohepatic circulation of indomethacin. On concomitant administration of 1200 mg of aspirin t.i.d., mean plasma levels of indomethacin were depressed by 20% after a single oral dose, by a smaller margin after multiple oral doses, and not at all after a single intravenous dose of indomethacin. The mean plasma concentration of orally administered indomethacin was decreased by 8% when given concurrently with a single 1200 mg dose of aspirin. Concomitant chronic therapeutic dosages of indomethacin had no effect on salicylate accumulation from repetitive doses of aspirin.     

Pharmacokinetics of FK027 in rats and dogs

The pharmacokinetics of FK027, a new oral cephalosporin, were investigated in rats and dogs and compared with those of cefaclor, cephalexin and amoxicillin. Upon oral administration to either rats or dogs, FK027 produced higher and more sustained serum levels than the reference drugs, hence a longer half-life. After both oral and intravenous administration, the half-life of FK027 in dogs was approximately three fold that in rats. Although the concentrations of FK027 in rat kidney, liver and spleen were lower than those of cephalexin and amoxicillin, they were sustained similarly to the serum levels. The 24-hour urinary and biliary recovery rates of FK027 in rats after oral dosing with 100 mg/kg were 34.1 and 21.9%, respectively. The urinary excretion of FK027 was significantly lower than that of the reference drugs, however, the biliary excretion was higher. In dogs, 23.4 and 0.2% of the given dose of 40 mg/kg of FK027 was excreted in the 24-hour urine and bile, respectively. Bioavailability of FK027 after oral dosing was 38% in rats and 47% in dogs, as calculated from intravenous data. Binding of FK027 to serum protein in all species was the highest of the test drugs: 63% for human, 93% for dog, 61% for rat serum.     

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children.

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUCO----infinity) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlag was less than ibuprofen, Ka was more than ibuprofen, and beta was less than ibuprofen. The ibuprofen beta was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUCO-----infinity was higher in the older (greater than or equal to 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUCO----infinity and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.     

The effect of diazepam in the recovery of rabbits from acute acetaminophen intoxication.

We have recently shown that diazepam can reduce mortality of acute iron overdose in rats. The mechanism for that effect is not yet defined. Our objective in the present study was to assess whether diazepam can similarly reduce mortality of experimental acute acetaminophen intoxication. Survival of rabbits was compared among four groups receiving 3 g/kg (body weight) of acetaminophen (LD40) orally each, followed by: 1) nothing (group I), 2) one oral dose of 140 mg/kg N-acetylcystein (NAC) an hour later (group II), 3) intramuscular injection of 7 mg/kg diazepam (group III), 4) intramuscular injection of 7 mg/kg diazepam and one oral dose of 140 mg/kg NAC an hour later (group IV). 37.5% of rabbits in group I died after 16 hours, whereas none of the rabbits in group III died, (p = 0.04). No animal died during the 96-hour observation period in groups II and IV. Two and four hours post drug administration, acetaminophen plasma concentrations (APC) were significantly lower among rabbits in group III than in group I (p = 0.0007 and 0.01, respectively) and significantly lower among rabbits in group IV than in those in group II (p<0.0001 and p = 0.03, respectively). Acetaminophen plasma concentrations 2 hours after drug administration were also significantly lower among rabbits in group III than in those in group II (p = 0.0002). Seven and 24 hours after dosage, APC tended to be higher among rabbits in group III than in those in group I, but not significantly so. Administration of diazepam without NAC did not prevent liver and renal dysfunction. We conclude that early administration of diazepam in acute experimental acetaminophen overdose in rabbits reduced APC and mortality, probably by slowing intestinal motility, which resulted in delayed acetaminophen absorption from the gastrointestinal tract.     

Pharmacokinetics of Levodopa and Carbidopa in Rats Following Different Routes of Administration

This study examined the pharmacokinetics of levodopa and carbidopa in the rat after different modes of administration. The drugs were given simultaneously by the intravenous, intraarterial, oral, duodenal, and intraperitoneal routes, as single doses. The ratio of levodopa to carbidopa given was always 4:1. Two iv doses (5 and 15 mg/kg of levodopa) were given to test for nonlinearity. Three ip doses of levodopa were given (5, 7.5, and 15 mg/kg), and the 15 mg/kg dose was given in three volumes (2, 4, and 20 mL/kg). One oral dose and two intraduodenal doses of 15 mg/kg were given. The drugs were dissolved in saline in one of the intraduodenal doses and suspended in 1.8% methylcellulose in the other. The elimination of levodopa was nonlinear. There was a comparatively high degree of interindividual variability in absorption with the oral route, but this was substantially reduced when levodopa was given intraduodenally. There was also much less variability with the intraperitoneal route compared to the oral, and the degree of absorption was generally high. There was a significantly higher extent and slower rate of absorption when levodopa was administered ip in a large volume of vehicle. These results suggest that the oral route may not be the optimal method of delivering levodopa to patients who have a fluctuating response and that a continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative.