Disposition of ceftriaxone in rat: application of a pharmacokinetic-protein binding model and comparison with cefotaxime

1. The pharmacokinetic profile and protein binding parameters of ceftriaxone were determined in rat, and compared with those of cefotaxime. 2. Plasma concentration-time curves of ceftriaxone and cefotaxime (single i.v. bolus; 100 mg/kg each) were described by a two-compartment, protein-binding model. 3. The corrected VTss (ml/kg) of ceftriaxone was lower than that of cefotaxime. The AUCs of both drugs were similar. The t1/2 beta of the two drugs differed significantly, being 29 min for ceftriaxone and 17 min for cefotaxime. 4. In vivo protein binding constants of both drugs were similar, but the concentrations of protein binding sites differed significantly. The average free fractions in plasma (Fp) of ceftriaxone and cefotaxime were 0.22 and 0.48 respectively. 5. Saturation of the binding site for cefotaxime was estimated to occur at about 30 micrograms/ml in plasma, whereas saturation for ceftriaxone was seen at lower concentrations.     

Pharmacokinetics and metabolism of NO-1886, a lipoprotein lipase-promoting agent, in cynomolgus monkey

1. The study was conducted to investigate the pharmacokinetics and metabolism of NO-1886 (diethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) in cynomolgus monkeys. 2. After single intravenous administration of NO-1886 at a dose of 3 mg kg(-1), the total clearance (CL(tot)), area under the plasma concentration-time curve (AUC(0-)(t)), half-life (t(1/2)), and volume of distribution (V(d)) in cynomolgus monkeys were 531 ml h(-1) kg(-1), 5.63 micro g h ml(-1), 0.96 h and 679 ml kg(-1), respectively. The AUC(0-)(t) for oral administration of NO-1886 (3 mg kg(-1)) was 4.23 micro g h ml(-1) and the bioavailability was 75%. 3. M-2 (ethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) and M-3 (4-[(diethoxy-phosphoryl) methyl)] benzoic acid) were present as metabolites in plasma and urine. In faeces, M-2 was present but M-3 was not. 4. The major metabolite of NO-1886 in liver S9 or microsomes was M-2 in the presence of NADPH. On the other hand, M-3 was formed in the absence of NADPH in liver S9 or microsomes and its formation was inhibited by bis-( p-nitrophenyl) phosphate (BNPP) in liver S9, suggesting that the formation of M-3 was catalysed by carboxylesterase. 5. The findings suggest that the main metabolic pathway of NO-1886 in cynomolgus monkeys is the O-deethylation of NO-1886 to M-2, as in rats and humans, and that the hydrolysis of the amide bond is a minor metabolic pathway.     

Cefotaxime disposition pharmacokinetics during peritoneal dialysis

The pharmacokinetics of cefotaxime and its main metabolite des-acetyl-cefotaxime were studied after a single 1000 mg intravenous dose in 8 patients with end stage renal disease during peritoneal dialysis. Pharmacokinetic parameters were determined by iterative non-linear least squares regression analysis of plasma and dialysis fluid drug concentration curves. Biological half-life of cefotaxime ranged from 2.3 to 8.2 hours and total plasma clearance from 11 to 103 ml/min. (0.11 to 1.7 ml/min/kg b.wt). Only 1.4% to 4.2% of the intravenous dose of cefotaxime was distributed to the dialysis fluid. We conclude that the dosage of cefotaxime to uraemic patients adjusted to the renal function needs no further adjustment during peritoneal dialysis.     

Effect of caffeine on ceftriaxone disposition and plasma protein binding in the rat

Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivo protein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100 mg/kg and caffeine 20 mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3-347 micrograms/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p less than 0.05) from 13.1 +/- 1.8 mg (mean +/- SD, 54.6% of total) to 15.3 +/- 1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC) was reduced from 612 to 516 micrograms hr/ml. Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUC values (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.     

Pharmacokinetics of oltipraz after intravenous and oral administration in rats with dehydration for 72 hours

Pharmacokinetic parameters of oltipraz were compared after intravenous and oral administration at a dose of 30 mg/kg to control rats and rats with water deprivation for 72 h (rats with dehydration). The plasma protein binding of oltipraz was measured in both groups of rats using an equilibrium dialysis technique. The concentrations of oltipraz were measured by the reported HPLC analysis. After intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), terminal half-life, time-averaged total body and nonrenal clearances, and apparent volume of distribution at steady state were not significantly different between the two groups of rats. However, after oral administration to rats with dehydration, the AUC was significantly smaller than that in control rats (180 versus 316 microg min/ml) mainly due to decrease in absorption. In rats with dehydration, plasma protein binding was significantly greater than that in control rats (91.5 +/- 0.309 versus 81.3 +/- 2.79%).     

Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat.

Pharmacokinetics of 4-hydroxycyclophosphamide (4-OHCP), the major active microsomal metabolite of cyclophosphamide (CP), were investigated in the Sprague-Dawley rat following separate iv bolus administrations of CP, synthetic 4-OHCP, and their combination. CP, 4-OHCP, and other metabolites such as phosphoramide mustard, alcophosphamide, and 3-(2-chloroethyl)-1,3-oxazolidin-2-one in rat plasma were simultaneously analyzed using GC/MS and stable isotope dilution techniques. Following iv administrations of 4-OHCP to rats at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg, phosphoramide mustard was found to be the major circulating metabolite followed by alcophosphamide and 3-(2-chloroethyl)-1,3-oxazolidin-2-one. No appreciable amount of nor-nitrogen mustard was detected in circulation. The mean excretion of unchanged 4-OHCP in two rats was 4.1 +/- 0.2% of the administered dose in 24-hr urine. Plasma concentration-time profiles of 4-OHCP declined monoexponentially with a mean half-life and total plasma clearance values of 8.1 min and 81.2 ml/min.kg, respectively. No dose-dependent kinetics were apparent between the 10 and 40 mg/kg doses used. The short half-life of 4-OHCP may be due partly to its degradation in plasma, which was found to be a first-order process in vitro with a half-life of 5.2 min. On the other hand, when CP was administrated to eight separate rats at 20 mg/kg each, the mean apparent elimination half-life for the derived 4-OHCP was 55.4 min as compared to 58.2 min, the mean elimination half-life for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic changes of oltipraz after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine

Pharmacokinetic changes of oltipraz were investigated after intravenous and oral administration at a dose of 30 mg/kg to control Sprague-Dawley rats and rats with liver cirrhosis induced by dimethylnitrosamine. After intravenous administration in rats with liver cirrhosis, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly greater (1490 microg min/ml versus 2840 microg min/ml) than that in control rats. This was due to significantly slower total body clearance (CL) (20.2 ml/(min kg) versus 10.6 ml/(min kg)) in the rats. The slower CL was due to significantly slower CL(NR) (20.1 ml/(min kg) versus 10.5 ml/(min kg)) in rats with liver cirrhosis. The significantly slow CL(NR) was due to slower hepatic blood flow rate and significantly slower in vitro intrinsic oltipraz disappearance clearance (CL(int), 77.2 ml/min per whole liver versus 11.5 ml/min per whole liver) because the free (unbound in serum proteins) fraction of oltipraz was significantly greater (15.1% versus 31.3%) in the rats. After oral administration in rats with liver cirrhosis, the AUC was also significantly greater (354 microg min/ml versus 812 microg min/ml) and this was not due to increased absorption in the rats. This also could be due to slower hepatic blood flow rate and significantly slower CL(int) in the rats.     

The alpha 2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP)

Ipsapirone and gepirone, analogs of buspirone, a newly developed antianxiety agent, form 1-(2-pyrimidinyl)-piperazine (PmP) during their biotransformation in rats. After oral administration (10 mg/kg) of a parent drug, e.g. ipsapirone or gepirone, the metabolite appears in significant amounts in plasma, with maximal concentrations of 0.9 and 1.4 nmol/ml respectively. The metabolite half-life ranged from about 140 to 200 min. Ipsapirone is eliminated more slowly than gepirone, with a half-life of about 100 and 30 min, respectively. The metabolite to parent drug ratios for the areas under the plasma concentration-time curve (AUC) were 1 for ipsapirone and 14 for gepirone. PmP (0.5-2 mg/kg p.o), ipsapirone, gepirone and buspirone (5-20 mg/kg p.o.) dose dependently antagonized the slowing of gastrointestinal transit induced by clonidine 0.1 mg/kg s.c. The doses inhibiting the antitransit effect of clonidine by 50% were 0.8 mg/kg for PmP, 14 mg/kg for ipsapirone and 9 mg/kg for both gepirone and buspirone. Analysis of small intestinal longitudinal muscle of rats given the ED50 of PmP, ipsapirone, gepirone, buspirone showed that PmP concentrations in the longitudinal muscle (with attached myenteric plexus) fell within a relatively narrow range and were consistent with the appropriate transit scores. The plasma was also tested for anticlonidine activity. These data indicate that PmP formation is a pharmacologically significant metabolic process for the buspirone-related drugs, ipsapirone and gepirone, and that this metabolite is responsible for the alpha 2-adrenoceptor blocking activity exerted by these drugs in vivo in the rat.     

Kinetic metabolism of vinpocetine in the rat

The pharmacokinetics of vinpocetine (Cavinton), a new potent vasodilator, and of its main metabolite have been studied in rats by specific extraction and radio thin-layer chromatography following i.v. and p.o. administration. The drug is rapidly eliminated, its half-life was found to be 125 min. The apparent volume of distribution was 3.8 l/kg and the clearance rate 33 ml/min/kg. From the equation describing the concentration-time curve a two-compartement open model was computed. Bioavailability of vinpocetine after p.o. administration was about 50%. The main metabolite, free apovincaminic acid, is formed very rapidly in rats and is eliminated from plasma with a half-life of 360 min.     

青蒿琥酯在奶牛体内的药代动力学与代谢

青蒿琥酯(artesunate,AS)是抗疟新药青蒿素的一个活性衍生物。近年来我国兽医工作者将其用于治疗牛羊泰勒氏焦虫病及双芽、巴贝斯焦虫病、鸡球虫病和耕牛血吸虫病,也收到了满意的效果。AS在大白鼠、兔、狗及人体内的药代动力学研究已见报道。本     

Gender differences in pharmacokinetics of oral warfarin in rats

Gender different pharmacokinetics of warfarin were investigated after oral administration at a dose of 2 mg/kg to male and female rats. The concentrations of warfarin in rat plasma were analysed by the HPLC method. Noncompartmental analysis was used for the calculation of the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and terminal half-life of warfarin. After oral administration of warfarin to female rats, the AUC was significantly greater (345 compared with 180 microg h/ml) than that in male rats.     

Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat

The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction

Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30-50mg (0.53 mg/kg bodyweight) over 5-10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase. Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17-24 minutes, and the mean terminal half-life was 65-132 min. Over the clinically relevant dose range of 30-50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V(1) was 4.2-6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1-9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V(1). Total bodyweight explained 19% of the variability in CL and 11% of the variability in V(1), and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL. The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC(2-90) exceeded 320 microg.min/ml, corresponding to an average plasma concentration of 3.6 microg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30-50mg was higher than for alteplase 100mg. Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.     

High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment

Several clinical studies have shown oral morphine and methadone to be effective in the treatment of intractable pain in patients with malignant disease. Recent pharmacokinetic studies have confirmed the rationale for regular administration of oral morphine and methadone but have revealed marked interindividual differences in the kinetics and metabolism which must be considered when titrating the oral dose according to the individual patient's need. Oral absorption of morphine in patients with malignant diseases is rapid, with peak plasma concentrations occurring at 20 to 90 minutes. Predose steady-state concentrations bear a constant relationship to dose, but vary considerably between individuals. The oral bioavailability is approximately 40% with marked patient-to-patient variations as a result of differences in presystemic elimination. The reported values for the volume of distribution range from 1.0 to 4.7 L/kg. Plasma protein binding is about 30%. The elimination half-life varies between 0.7 and 7.8 hours. Plasma clearance is approximately 19 ml/min/kg (5 to 34 ml/min/kg) and mostly accounted for by metabolic clearance. Studies in a few patients with malignant diseases treated regularly with daily doses of oral morphine ranging from 20 to 750mg indicate a linear relationship between the dose and trough concentration of morphine. Long term treatment with 10- to 20-fold increase of the oral dose over a period of 6 to 8 months does not seem to change the kinetics of oral morphine. The plasma concentrations of the main metabolite, morphine-3-glucuronide (M3G), exceed those of the parent drug by approximately 10-fold after intravenous administration and by 20-fold after oral administration. The relationship between the area under the plasma concentration-time curve (AUC) of morphine and the AUC of morphine-3-glucuronide remains constant during the development of tolerance upon long term treatment with increasing doses. Renal disease causes a significant increase in the mean plasma concentrations of morphine for 15 minutes after its administration, while mean values of terminal half-life and total body clearance are within the normal range. However, the glucuronidated polar metabolite morphine-3-glucuronide rises rapidly to high concentrations which persist for several days. Chronic liver disease causes an increase in the bioavailability of oral morphine but no, or only a slight reduction in the intravenous clearance. The elimination half-life and volume of distribution are within the normal range.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of acute renal failure on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). After intravenous administration in rats with U-ARF, the time-averaged total body clearance (Cl) was significantly faster (2.45 versus 0.932 ml/min/kg) than controls due to significantly faster nonrenal clearance (2.25 versus 0.855 ml/min/kg) in rats with U-ARF. The faster nonrenal clearance could be due to significantly greater gastrointestinal (including biliary) excretion; the amount of unchanged DA-7867 recovered from the entire gastrointestinal tract at 24 h was significantly greater (30.3% versus 9.38% of intravenous dose) in rats with U-ARF. In rats with U-ARF, the Vss was significantly larger (1420 ml/kg compared with 580 ml/kg), but this was not due to a difference in plasma protein binding; the values were comparable between the two groups of rats. After oral administration to rats with U-ARF, the total area under the plasma concentration-time from time zero to time infinity (AUC) of DA-7867 was significantly smaller than the controls (2560 microg min/ml versus 7440 microg min/ml), and this was not due mainly to a decrease in absorption from the gastrointestinal tract in rats with U-ARF.     

Pharmacology of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (VI). Determination of metabolites in monkey plasma by combined high-performance liquid chromatography and enzyme immunoassay

A new sleep-inducer, 450191-S, was orally administered to two old rhesus monkeys and three young ones at a pharmacologically active dose (1 mg/kg). The area under the plasma concentration versus time curve (AUC) of M-1 was the smallest among the measured metabolites. The AUC of M-2 in the old monkeys was 10 times higher than that of the young ones. M-A was one of the major metabolites, and its AUC in the old monkeys was also four times higher than that in the young ones. The AUC of M-3 was the largest among the measured metabolites. The time of maximum concentration was 12-16 hr after dosing; and thereafter, the concentration decreased gradually with a 12-hr half-life. The M-4 level was constantly low during 24 hr after dosing and then decreased gradually. The active metabolite M-1 was also administered to the two young monkeys at a dose of 0.73 mg/kg, and the time course of the plasma concentration of metabolites was compared with that after 450191-S administration to the young monkeys, because 450191-S may be changed to M-1 in the process of intestinal absorption. The concentration of M-1 was extremely low in spite of the dosing of M-1 itself, and the AUC of M-1 was one-sixth of that after 450191-S administration. The concentration of M-2 was also low, and its AUC was one-third of that after 450191-S administration. The AUC's of M-A, M-3 and M-4 were not very different from those after 450191-S administration. These results indicated that there is an age-related difference in the plasma concentration of M-2 and M-A when 450191-S is administered orally and that the plasma concentrations of M-1 and M-2 differ greatly between 450191-S and M-1 administrations.     

Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effect.

The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration-time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 microg min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC(0-12 h) at 50 mg/kg (25.1, 18.3 and 49.2 microg min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 microg min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats.     

Pharmacokinetics of a new histamine H2-receptor antagonist, Z-300, in rat and dog.

1. The plasma level of Z-300 reached a maximum (Cmax) at 30 min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a half-life of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3 mg/kg. At doses ranging from 3 to 30 mg/kg, Cmax and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached Cmax at 10 min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10 mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50 mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of alpha1-acid glycoprotein (alpha1-AG), because Z-300 bound more strongly to alpha1-AG than to albumin.     

Pharmacokinetics and biotransformation of the cyclosporine metabolite M-17 in the rabbit

The monohydroxylated cyclosporine (CsA) metabolite M-17 was isolated from bile of human liver transplant recipients by preparative HPLC. The structure and purity of the metabolite were confirmed by fast atom bombardment-mass spectroscopy and proton NMR. The isolated metabolite was administered iv to three rabbits at a dose of 1.0 mg/kg with the following mean pharmacokinetic parameters being determined: half-life (t1/2B) 2.22 hr, volume of distribution (Vss) 1.44 liters/kg, and clearance 11.07 ml/min/kg. These are not significantly different from those obtained for CsA. In bile and urine obtained from rabbits administered M-17, the CsA metabolites M-8, M-18, and M-26 were found, indicating that M-17 is further metabolized. The latter data support the proposed biotransformation pathways for M-17.     

Pharmacokinetic changes of DA-8159, a new erectogenic, after intravenous and oral administration to rats with acute renal failure induced by uranyl nitrate

The pharmacokinetic parameters of DA-8159, a new erectogenic, were compared after intravenous and oral administration of the drug at a dose of 30 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (U-ARF). After intravenous administration to rats with U-ARF, the plasma concentrations of DA-8159 were higher than those in control rats. This resulted in a significantly greater area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 in rats with U-ARF (304 compared with 365 microg min/ml for control rats and rats with U-ARF). The significantly greater AUC in rats with U-ARF was due to significantly slower total body clearance (Cl) of DA-8159 (98.6 compared with 82.2 ml/min/kg). The significantly slower Cl in rats with U-ARF was due to slower renal clearance (1.07 ml/min/kg compared with not calculable, due to impaired kidney function) and nonrenal clearance (97.5 compared with 82.2 ml/min/kg due to slower metabolism) than those in control rats. After oral administration of DA-8159 to rats with U-ARF, the AUC (122 compared with 172 microg min/ml) was significantly greater and Cl(R) was slower (3.47 ml/min/kg compared with not calculable) than those in control rats. The significantly greater AUC in rats with U-ARF could be due to slower Cl of DA-8159 in the rats.