Kinetics of biliary elimination of pentacaine in rats

Pentacaine, a local anaesthetic of the carbanilate type, administered intravenously as 3H-pentacaine, 2 mg kg-1 to rats, was eliminated in the bile mainly in the form of metabolites (20.5 +/- 1.5 per cent of the dose) and as parent drug (0.1 per cent of the dose) within 3 days. In control rats 32.2 +/- 2.5 and 37.8 +/- 2.5 per cent of 3H-dose, representing pentacaine metabolites, were excreted in the urine and faeces, respectively. In bile-duct-cannulated rats 35.7 +/- 6.8, 11.2 +/- 3.4, and 20.5 +/- 1.5 per cent of 3H-dose were excreted in the urine, faeces, and bile, respectively. The high 3H recovered in faeces in animals with diverted bile flow indicated passage of pentacaine metabolites through the intestinal wall. The excretion of pentacaine and its metabolites in bile was an active process, since the ratio bile/plasma concentration rapidly attained values approaching 10. In rats with ligated ureters the biliary elimination of pentacaine and its metabolites was enhanced, compensating for impaired urinary excretion. This was accompanied by increased plasma and brain levels of 3H compared with untreated controls.     

Pharmacokinetics of pafenolol after i.v. and oral administration of three separate doses of different strength to man

The pharmacokinetics of pafenolol were evaluated in 12 healthy subjects after administration of three single IV doses (5, 10, and 20 mg) and three oral single doses (25, 50, and 100 mg). The drug was discontinuously absorbed. A first peak was observed 0.5 to 1.5 h after dosing and a second higher maximum concentration was noted 3 to 5 h after the administration in the majority of the experiments. The mean systemic availability increased from 27 +/- 5 per cent for the oral 25 mg dose to 46 +/- 5 per cent for the 100 mg dose, i.e., an increase of about 70 per cent (p less than 0.05). The half-life of distribution varied between 5 and 6 min and the apparent volume of distribution (Vz) was about 1.11 kg-1. The distribution was linear in the IV dose range studied. Total body clearance was about 300 ml min-1. About 50 per cent of the systemically available dose was excreted unchanged via the kidneys. Total body clearance decreased by about 13 per cent (p less than 0.05) by increasing the dose from 5 to 20 mg IV possibly because of reduced renal elimination. Mean terminal t1/2 of the IV dose was approximately 3.5 h. The corresponding t1/2 of the oral dose was approximately 6 h indicating absorption rate-limited kinetics of the oral dose.     

The pharmacokinetics of HI-6 in beagle dogs

The pharmacokinetics of HI-6 were studied following intravenous administration to beagle dogs (n = 7). The bioavailability of two different strength intramuscularly administered doses was also determined in the same animals. After a 20 mg kg-1 intravenous dose, the mean (+/- S.D.) initial HI-6 plasma concentration was 93.1 +/- 10.8 micrograms ml-1. The mean half-life was 48.2 +/- 17.7 min, the mean total body clearance was 5.16 +/- 0.81 ml min-1 kg-1, the mean apparent volume of distribution was 0.37 +/- 0.20 l kg-1 and 61.2 +/- 14.6 per cent of the dose was excreted as unchanged drug. The pharmacokinetic constants calculated following the 20 mg kg-1 intramuscular doses of 250 and 25 mg ml-1 solutions were not significantly different from those obtained following the intravenous dose. Also, the areas under the plasma concentration versus time curves were not significantly different indicating 100 per cent bioavailability from the intramuscular route of administration.     

多索茶碱在大鼠体内的药代动力学

为全面了解多索茶碱在大鼠体内代谢情况,用高效薄层色谱法和光密度扫描法,给大鼠ig多索茶碱后,测定在不同时间各组织和体液中多索茶碱的含量。结果表明,多索茶碱在大鼠体内药代动力学为一室模型并能在体内迅速转化为其它代谢产物。T_1/2(Ke)为1.17～3.75h,达峰时间T(peak)为0.72～1.46h,Cmax,AUC及CL/F呈剂量依赖关系。给药1h,以胃壁浓度最高,8h除胃肠组织浓度降低较慢外,其它组织中药物浓度明显降低。尿、粪及胆汁中原形药总排出量占给药量的5.2%。血浆蛋白结合率约25%。提示多索茶碱在体内可能转化为其它代谢产物。     

Dose-dependent pharmacokinetics of zoxazolamine in the rat

Zoxazolamine (ZX) is a model substrate frequently used in studies on (methylcholanthrene-inducible) hepatic cytochrome P-450 activity. The iv pharmacokinetics of ZX were studied in rats at four dose levels: 5 mg X kg-1 (n = 6), 25 mg X kg-1 (n = 6), 50 mg X kg-1 (n = 5), and 60 mg X kg-1 (n = 4). Concentrations of ZX in blood, as well as the urinary excretion of unchanged ZX and chlorzoxazone, were determined. The apparent systemic clearance (CLs,app) decreased with increasing dose from 52.6 +/- 3.9 at 5 mg X kg-1 to 9.3 +/- 0.4 ml X min-1 X kg-1 at 60 mg X kg-1. The apparent elimination half-life, t1/2,app, increased from 16.1 +/- 0.3 min to 141 +/- 28.5 min. There was only slight concentration dependency of plasma protein binding: 86.0 +/- 0.9% at 4.2 +/- 0.2 micrograms X ml-1 (n = 6) vs. 80.4 +/- 0.4% at 27.1 +/- 1.1 micrograms X ml-1 (n = 6). Since from clearance and protein binding data nonrestrictive clearance of ZX could be inferred, this small change in binding was regarded as irrelevant for the interpretation of pharmacokinetic data of ZX. The blood-plasma concentration ratio was larger than unity: 2.11 +/- 0.09 at 5.4 +/- 0.9 micrograms X ml-1, and 1.85 +/- 0.08 at 47.9 +/- 4.9 micrograms X ml-1 (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of co-administration of Intralipid on the pharmacokinetics of cyclosporine in the rabbit

The effect of Intralipid co-administration on the pharmacokinetics of cyclosporine (CyA) was studied in NZW rabbits. A single intravenous bolus dose of CyA (10 mg kg-1) mixed with 3 ml of Intralipid was administered to rabbits (n = 4). Control animals (n = 4) received the same dose of CyA without Intralipid. Serial blood samples were collected up to 12 h after the administration of CyA. Concentrations of CyA in plasma were analyzed using a HPLC method. The terminal elimination half-life (t1/2) of CyA was significantly lower with Intralipid administration (191 +/- 25 min) than control (298 +/- 59 min). The total body clearance (ClTOT) and volume of distribution (Vdss) of CyA was reduced by approximately 65-70 per cent with Intralipid administration compared to control. The free fraction of CyA in plasma with and without Intralipid administration was estimated to be 0.05 +/- 0.01 and 0.17 +/- 0.06, respectively. Co-administration of Intralipid with CyA decreased both the ClTOT and Vdss resulting in a rapid elimination, i.e., decrease in a t1/2 of CyA from the body.     

Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats.

The pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats was investigated following intravenous administration of the drug. Mean residence time and steady state volume of distribution were 23-36 min and 0.20-0.311 kg-1, respectively, and were dose independent at the dose of 0.3-3 mumole kg-1. Total body clearance of 8.2 ml min-1 kg-1 over 0.3 mumole kg-1 was slightly increased to 11.3 ml min-1 kg-1 at 3 mumole kg-1. Renal clearance was also increased with the increase of the dose, while hepatobiliary clearance was substantially constant. Ambenonium was highly concentrated in the liver, kidney, spleen, and lung. About 30 per cent of the dose is concentrically stored in the liver at 6 h after administration, and had not disappeared after 24 h.     

Species differences in the pharmacokinetics of recainam, a new anti-arrhythmic drug

The pharmacokinetics of recainam, an anti-arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man. Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non-linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mg kg-1 oral doses and rhesus monkeys between 1 and 15 mg kg-1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54-208 mg kg-1 in mice, 25-110 mg kg-1 in rats, and 50-100 mg kg-1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1-5h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (l kg-1 .h) was 4.9-5.2 in rats and rabbits and 0.4-1.9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2-5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10-45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6 h post-dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.     

Pharmacokinetics and pharmacodynamics of physostigmine in the rat after oral administration

The distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of 3H-Phy (650 micrograms kg-1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one-compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0.1 +/- 0.07 min-1 and 0.036 +/- 0.024 min-1, respectively. Cpmax and tmax were 3.3 ng ml-1 and 16 min. The clearance (C1) was found to be 80.9 ml min-1kg-1. Half-life of Phy in brain, muscle, and liver were 33.4 min, 22.5, and 28 min, respectively. The bioavailability (F) was calculated to be 0.02 and the extraction ratio was found to be 0.98 indicating the 'first pass' effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2.89 ng ml-1 at 15 min and declined to 0.71 ng ml-1 at 90 min. Physostigmine concentration in brain peaked at 22 min to 2.85 +/- 1.09 ng g-1 and declined to 0.33 +/- 0.11 ng g-1 at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66.4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94.6 per cent in plasma, 90 per cent in liver, 79.8 per cent in brain and 86.3 per cent in muscle. M1 appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous studies with the same dose after i.m. administration.     

Pharmacokinetics and bioavailability of the anti-emetic agent bromopride

The pharmacokinetics of bromopride, an anti-emetic agent chemically related to metoclopramide, has been investigated in normal human subjects. After intravenous bolus doses of 10 mg, a one-compartment open model appeared adequate to describe the plasma drug concentration data. The systemic clearance of bromopride was 899 ml min-1 +/- 22 per cent CV, the volume of distribution was 2151 +/- 16 per cent CV, and the elimination half-life was 2.9 h +/- 21 per cent CV. Over a wide drug concentration range of up to 650 ng ml-1, bromopride was only 40 per cent bound to plasma proteins. The systemic availability of orally and intramuscularly administered solution doses of 20 mg of bromopride was 54 per cent and 78 per cent, respectively. Formulation of bromopride as the solid material in capsules delayed absorption but did not affect the extent of drug bioavailability. The pharmacokinetics of bromopride appeared similar to that of metoclopramide. No evidence for non-linear kinetics was found when bromopride was administered orally in the dose range 10-30 mg: after single oral doses of 10, 20, and 30 mg, peak mean plasma drug concentrations were 20 ng ml-1 +/- 32 per cent CV, 38 ng ml-1 +/- 16 per cent CV, and 64 ng ml-1 +/- 23 per cent CV, respectively.     

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg-1. 2. Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 +/- 9.6 ml min-1 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. The mean residence time and half-life were 20.9 +/- 1.4 and 14.4 +/- 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 +/- 0.18 l kg-1. 3. No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4. In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5. These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.     

Pharmacokinetics of tiazofurin in dogs

The pharmacokinetics of total and free tiazofurin, an antineoplastic agent, was studied in healthy mongrel dogs following intravenous and oral administration of the drug. The free fraction of tiazofurin was obtained from plasma by an ultrafiltration technique using a micropartition system. Total and free tiazofurin levels were determined by a sensitive high performance liquid chromatographic method. The percentage of tiazofurin bound to plasma proteins remained constant at approximately 15 per cent following administration to healthy mongrel dogs. The mean pharmacokinetic parameters of elimination rate constant (K), effective half-life (t 1/2), mean residence time (MRT) and the time to reach peak plasma level (tmax--after oral administration) were 0.32 +/- 0.04 h-1, 2.24 +/- 0.25 h, 3.23 +/- 0.36 h, and 1.78 +/- 0.50 h, respectively. The apparent volume of distribution at steady state was 0.98 +/- 0.30 1 kg-1 and the plasma clearance was 5.24 +/- 2.39 ml min-1 kg-1. About 90 per cent of tiazofurin was absorbed following oral administration. The pharmacokinetic parameters did not differ significantly between the total and free drug levels, indicating that the pharmacokinetics of total tiazofurin levels reflect those of the free tiazofurin in plasma.     

Pharmacokinetics and oral bioavailability of carbimide in man

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0.1, 0.3, 0.6, and 1 mg kg-1 and linear pharmacokinetics were observed for this dose range. Elimination half-life and total plasma clearance values ranged from 42 to 52 min and from 14.4 to 20.5 ml kg-1 min-1, respectively. After oral administration of 1 and 1.5 mg kg-1 of carbimide, elimination half-life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0.3 mg kg-1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10.5 to 15.5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0.3 and 1 mg kg-1 carbimide dose, respectively. The data indicate that there is a first-pass effect for carbimide.     

Pharmacokinetics of eltoprazine in the dog

Pharmacokinetics of eltoprazine in male and female beagle dogs was studied in two separate cross-over experiments after administration of different intravenous and oral doses. After intravenous administration of 0.5 mg.kg-1, the mean volume of distribution was 5.7 +/- 1.1 l.kg-1. Clearance was 25.5 +/- 1.4 ml.min-1.kg-1. About 25% of the doses was excreted in urine, resulting ina renal clearance of 6.1 +/- 1.4 ml.min-1.kg-1. The mean elimination half-life (t1/2) after intravenous dosing was about 2.6 h. After oral dosing the plasma peak levels (Cmax) were proportional with the dose. The mean time to reach Cmax (tmax) varied between 1.5 and 1.9 h, and t1/2 was about 2.4 h, which was not significantly different (p greater than 0.05) from the half-life obtained after intravenous dosing. Plasma pharmacokinetics after single and multiple dosing of 4 mg.kg-1 showed no difference. Absolute bioavailability was 67% +/- 20%.     

Absorption and disposition of fluvastatin, an inhibitor of HMG-CoA reductase, in the rabbit.

The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg-1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first-pass effect, its absolute bioavailability being 46 per cent. The steady-state volume of distribution of fluvastatin was 0.29 +/- 0.04 l kg-1 while the total body clearance was 0.33 +/- 0.05 1 h-1 kg-1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28 +/- 4 per cent of the oral dose and 32 +/- 3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg-1 day-1 beginning day 6 post-conception (p.c.), steady-state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25-50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0.92 and 0.97, respectively, on day 10 p.c. to 0.10 and 0.04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel decline, suggesting no tissue retention of the drug.     

Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.     

Distribution kinetics of FK-506, a novel immunosuppressant, after intravenous administration to rats in comparison with cyclosporin A.

The distribution kinetics of a novel potent immunosuppressant, FK-506 (FK) has been studied in comparison with cyclosporin A (CyA) both in vivo and in vitro using blood specimens. The infusion studies on FK, 5.0 mg kg-1 through the portal and femoral veins showed that the mean hepatic extraction ratio of FK was 27.9 per cent. The effect of clamping both the hepatic artery and the portal vein on the plasma disappearance profiles of FK, 5.0 mg kg-1, and CyA, 3.5 mg kg-1 was studied. The plasma disposition kinetics of CyA was almost the same as in the normal rats. However, the plasma FK levels were about 10 times higher than those obtained in the control group rats. This difference is attributed to the restricted initial distribution of FK to the liver, because the volume of the initial distribution space, V1, of FK was about 10 times smaller than that obtained in normal rats. In in vitro experiments, drug distribution was studied in blood samples (2.0 ml) spiked with FK or CyA, 1.0 micrograms ml-1. The plasma drug levels measured at 2 min after drug administration were 0.842 +/- 0.012 micrograms ml-1 and 0.769 +/- 0.047 micrograms ml-1 for FK and CyA, respectively. The distribution volume in the blood compartment, VB, was determined by dividing the spiked amount of drugs with these plasma concentrations. The VB was 2.38 +/- 0.04 ml for FK and 2.62 +/- 0.16 ml for CyA. There was no significant difference in VB between FK and CyA. The plasma free fraction, fp of the drugs was measured by the equilibrium dialysis method. For FK, the mean fp values (+/- SE) were 1.31 +/- 0.18 per cent (2.0 micrograms ml-1) and 1.93 +/- 0.18 per cent (5.0 micrograms ml-1). For CyA, the fp values were 4.85 +/- 0.36 per cent (1.0 micrograms ml-1) and 5.75 +/- 0.82 per cent (5.0 micrograms ml-1). The hydrophobicity parameter, logP' determined through the HPLC method was 0.386 for FK and 0.545 for CyA. Although FK was less hydrophobic than CyA, its protein binding was higher than CyA.     

Pharmacokinetics and thrombolytic properties of a nonglycosylated mutant of human tissue-type plasminogen activator, lacking the finger and growth factor domains, in dogs with copper coil-induced coronary artery thrombosis

The pharmacokinetics and thrombolytic properties of a variant of human tissue-type plasminogen activator (t-PA), obtained by deletion mutagenesis of the NH2-terminal fibronectin-like finger (F) and epidermal growth factor (E) domains, and substitution of the three known glycosylated Asn residues by Gln (t-PA-delta FE3X), were studied in dogs with a copper coil-induced thrombosis of the left anterior descending coronary artery. Bolus injections were given during 2 min to groups of three dogs. Injection of 0.15 mg/kg resulted in peak antigen levels in plasma of 1.58 +/- 0.72 micrograms/ml (mean +/- SEM) and caused reperfusion within 14 +/- 6 min. With 0.075 mg/kg, corresponding values of 0.81 +/- 0.20 micrograms/ml and 31 +/- 15 min were obtained. A bolus of 0.038 mg/kg yielded plasma peak levels of 0.43 +/- 0.20 micrograms/ml but did not cause coronary recanalization within 3 h. A bolus injection of natural t-PA (Mel-t-PA) at a dose of 0.1 mg/kg in four dogs resulted in plasma peak levels of 0.46 +/- 0.09 micrograms/ml and caused partial coronary artery reperfusion within 3 h in one of four dogs (after 31 min). None of these injections caused a significant decrease of the fibrinogen level. Pharmacokinetic parameters for t-PA-delta FE3X were alpha half-life (t1/2) 14-18 min, beta t1/2 72-125 min, and plasma clearance 21-36 ml/min. For Mel-t-PA, the corresponding values were 3 min, 8 min, and 520 ml/min. We conclude that the variant t-PA-delta FE3X has a markedly longer plasma t1/2 than does Mel-t-PA and, when administered as a bolus injection, a higher thrombolytic efficacy.     

Single dose pharmacokinetics of tiaprofenic acid. Effects of food and severe renal insufficiency

The single oral dose pharmacokinetics of tiaprofenic acid (Surgam) has been investigated in fasting and non-fasting healthy volunteers (200 and 300 mg) and in fasting patients with severe renal insufficiency (200 mg). A dose independent pharmacokinetics of tiaprofenic acid was shown in fasting healthy volunteers and the following parameters were calculated after administration of 200 mg: tl = 0.53 +/- 0.15 h, tm = 1.28 +/- 0.19 h, cm = 27.1 micrograms/ml, ka = 2.79 +/- 0.93 h-1, lambda 2 = 1.06 +/- 0.14 h-1, t1/2 = 3.0 +/- 0.2 h, AUCl-infinity = 80 +/- 7 mg X h/l, Clt = 43.8 +/- 3.7 ml/min and V beta = 11.1 +/- 0.8 l. A small, but significant positive deviation from linearity was observed with increasing dose for cm and AUCl-infinity in non-fasting healthy volunteers, probably due to a slightly higher bioavailability of the 300 mg formulation in the non-fasting state as compared with the 200 mg formulation. Intake of food decreased cm significantly at both dosage levels from 27.1 to 19.1 micrograms/ml and from 47.9 to 39.1 micrograms/ml for 200 and 300 mg, respectively. The absorption kinetics of tiaprofenic acid was not significantly different in fasting healthy volunteers and in fasting patients with severe renal insufficiency. However, a significant increase in t1/2 and AUCl-infinity to 5.8 +/- 0.9 h and 173 +/- 34 mg X h/l, respectively, and a significant decrease in total body clearance to 25.5 +/- 5.3 ml/min were observed in this category of patients. No correlation was found between creatinine clearance and tiaprofenic acid clearance.     

Disposition of gamma-glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg-1 and 100 micrograms kg-1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/- 1.50 ml min-1 kg-1 and 4.92 ml min-1 kg-1 at the higher and lower doses, respectively. Corresponding half-lives were 29.2 +/- 3.7 min and 32.5 +/- 5.6 min, and volumes of distribution were 0.183 +/- 0.052 l kg-1 and 0.235 +/- 0.07/ l kg-1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro-drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.