Validation of high-performance liqid chromatography method to determine epirubicin and its pharmacokinetics after intravenous bolus administration in rats

We investigated the pharmacokinetics of epirubicin, an anthracycline derivative antibiotics, after intravenous (i.v.) bolus administration in rats. To analyze epirubicin levels in the plasma, bile, urine and tissue samples, we developed an high-performance liqid chromatography (HPLC)-based method which was validated for a pharmacokinetic study by suitable criteria. The plasma concentration of epirubicin after i.v. bolus administration was rapidly disappeared within 10 min from the blood circulation. The mean plasma half-lives at α phase (t_1/2α) when administered at the dose of 2, 5, 10, 25 and 50 mg/kg were 2.14–2.61 min. The values of t_1/2β at the corresponding doses increased two folds (from 150 to 291 min) with increasing doses. The CL_t values significantly decreased with the increase in dose. In contrast, V_dss values increased about 1.5 times with the increase in dose from 2 to 50 mg/kg. Of the various tissues, epirubicin mainly distributed to the kidney, lung, heart and liver after i.v. bolus administration. The epirubicin concentrations in various tissues at 24 h after i.v. bolus administration were below 1.0 μg/g tissue. Epirubicin was excreted largely in the bile after i.v. bolus administration at the dose of 2, 10 and 50 mg/kg. The cumulative amount of epirubicin in the urine 72 h after dosage represented 20 % of the amount excreted in the bile 12 h after high dosage, indicating that i.v. administered epirubicin was mainly excreted in the bile. In conclusion, epirubicin was rapidly cleared from the blood circulation and transferred to tissues such as the kidney and liver 2 h after i.v. bolus administration. Moreover, the majority of epirubicin appears to be excreted in the bile by 12 h after i.v. bolus administration.     

The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs.

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [(14)C]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [(14)C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C(max) occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [(14)C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-hydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-beta-D-glucuronide (urine), trans-3, 4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).     

HPLC analysis and pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, in rats and beagle dogs

We investigated the pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration in rats and beagle dogs. We developed an HPLC-based method to analyze ID-6105 levels in plasma, bile, urine, feces, and tissue homogenates and validated the method in a pharmacokinetic study. The plasma concentration of ID-6105 decreased to below the quantifiable limit (0.02 microg/ml) at 4 and 8 h after i.v. administration in rats at doses of 2 and 10 mg/kg, respectively (t(1/2,alpha) and t(1/2,beta) of 0.78 and 17.8 min at a dose of 2 mg/kg, 0.91 and 176 min at a dose of 10 mg/kg, respectively). The AUC increased with nonlinear pharmacokinetics following the dosage increase from 2 to 10 mg/kg in rats, while the pharmacokinetics were not significantly altered in beagle dogs following a dosage increase from 0.5 to 2.5 mg/kg. Of the various tissues tested, ID-6105 was mainly distributed in the lung, spleen, kidney, adrenal gland, and liver after i.v. bolus administration. ID-6105 levels in the lung or kidney 2 h after i.v. bolus administration were comparable to the initial plasma concentration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration became too small to measure. The cumulative amounts of ID-6105 found in the bile 48 h after the administration of 2 and 10 mg/kg were calculated to be 26.7 and 18.5% of the initial dose, respectively. The corresponding values in the urine 72 h after i.v. administration were 4.33 and 3.07% of the initial dose, suggesting that ID-6105 is mostly excreted in the bile. In conclusion, our observations indicate that ID-6105 was rapidly cleared from the blood and transferred to tissues such as the lung, spleen, kidney, and liver 2 h after i.v. bolus administration. Moreover, the majority of ID-6105 appears to be excreted in the bile by 24 h after i.v. bolus administration.     

Pharmacokinetics of magnesium glycyrrhizinate following intravenous administration of magnesium glycyrrhizinate in rats.

The elimination, distribution, excretion of magnesium glycyrrhizinate (MG) after intravenous (i.v.) administration in rats, and the binding rate of MG to plasma protein were investigated. The concentrations of MG in plasma, tissue, and excretion of rats after i.v. administration of MG were measured using reversed-phase high performance liquid chromatography (RP-HPLC). The concentrations of MG in plasma declined in an apparent biexponential manner. The pharmacokinetic parameters from a two-compartment model analysis of plasma samples after i.v. administration of MG 30, 60, and 120 mg/kg-, were t(1/2beta) (min): 140, 180, and 240; AUC(0 approximately 18) (g x min x L(-1)): 10212, 15432, and 50321; CL (L x kg(-1) x min(-1)): 0.0025, 0.0039, and 0.0021, respectively. The drug administered as an iv injection, were mainly cumulated in the liver. When MG was administered to bile-duct cannulated rats, about 90% of i.v. dosed MG was excreted into bile under unchanged form within 24 h after administration. The average binding rate of MG to plasma protein was 87%. The experimental results showed that the distributional property of MG in the present rats study is beneficial to its liver protective activity and liver function improvement.     

Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats.

Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 407 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2. 5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers.     

Pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after i.v. bolus multiple administration in rats

We investigated the pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration at a multiple dose every 24 h for 5 days in rats. To analyze ID-6105 levels in biological samples, we used an HPLC-based method which was validated in a pharmacokinetic study by suitable criteria. The concentrations of ID-6105 after the multiple administration for 5 days were not significantly different from the results after the single administration. The t1/2alpha, t1/2beta, Vdss, and CLt after the multiple administration were not significantly different from the values after the single administration. Moreover, the concentrations of ID-6105 1 min at day 1-5 after i.v. bolus multiple administration did not show the significant difference. Of the various tissues, ID-6105 mainly distributed to the kidney, lung, spleen, adrenal gland, and liver after i.v. bolus multiple administration. ID-6105 concentrations in the kidney or lung 2 h after i.v. bolus administration were comparable to the plasma concentration shortly after i.v. bolus administration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration decreased to low levels. ID-6105 was excreted largely in the bile after i.v. bolus multiple administration at the dose of 3 mg/kg. The amounts of ID-6105 found in the bile by 12 h or in the urine by 48 h after the administration were calculated to be 14.1% or 4.55% of the initial dose, respectively, indicating that ID-6105 is mostly excreted in the bile. In conclusion, ID-6105 was rapidly cleared from the blood and transferred to tissues, suggesting that ID-6105 might not be accumulated in the blood following i.v. bolus multiple dosages of 3 mg/kg every 24 h for 5 days. By 48 h after i.v. bolus administration, ID-6105 concentrations in various tissues had decreased to very low levels. The majority of ID-6105 appears to be excreted in the bile.     

Pharmacokinetic study of triptolide, a constituent of immunosuppressive chinese herb medicine, in rats

Triptolide is a potential anti-immune agent, and has shown multi-organic toxicity, however its toxic mechanism remained undiscovered. This paper aimed at characterizing the pharmacokinetic profiles of triptolide in rats to provide the clue to approach the toxic mechanism. The absorption, distribution, metabolism and excretion of triptolide were investigated in male Sprague-Dawley rats after single doses of oral and i.v. administration. After oral administration of 0.6, 1.2 and 2.4 mg/kg, the concentration of triptolide in plasma reached the maximum within 15 min, and declined rapidly with an elimination half-life from 16.81 to 21.70 min. The triptolide kinetics was fitted into one-compartment model after i.v. administration. Oral absolute bioavailability was 72.08% at the dose of 0.6 mg/kg. Triptolide was also rapidly distributed and eliminated in all selected tissues. Less than 1% triptolide of the dose was recovered from the bile, urine or feces as parent drug within 48 h. While triptolide could not be detected in tissues and plasma at 4 h post dose, rats in the group C (oral: 1.2 mg/kg) and D (oral: 2.4 mg/kg) showed obvious toxic response to triptolide and some of rats even died out. It was indicated that triptolide was metabolized extensively, eliminated rapidly, and also showed that the toxicity produced by the triptolide was lag behind the exposure concentration.     

The diffusion of cefazedone into heart muscle, prostatic and skin tissue and into bile

The diffusion of cefazedone into human heart muscle, prostatic and skin tissue as well as bile fluid was investigated. 40 to 80 min after a single injection of 100 mg/kg (n = 14) the concentration in the heart muscle was between 10.8 and 85.5 micrograms/g. The respective serum levels were between 117 and 168.1 micrograms/ml. The single i.v. injection of 2 g cefazedone resulted within 30 min in a mean concentration of 34.63 +/- 9.75 micrograms/g in the prostatic tissue and in serum levels of 139.07 +/- 39.68 micrograms/ml (n = 14). In 5 patients additional values were estimated after 60 min. At this time the antibiotic concentrations were 24.92 +/- 1.31 micrograms/g in the tissue, with simultaneous serum levels of 87.25 +/- 20.86 micrograms/ml. 1 h after a 500 mg i.v. dose, concentrations in bile taken from T-tube were between 71.4 and 210 micrograms/ml. After 2 h there was a mean level of 83.2 micrograms/ml which was significantly above the serum concentrations at the same time (1 h = 35.25 +/- 7.17; and 2 h = 20.5 micrograms/ml). The bile concentration of 2 patients taken 5 h after cefazedone injection was 4.95 and 11.6 micrograms/ml. The cefazedone concentrations in the skin were estimated mainly in biopsies from granulating leg ulcer tissues. The mean concentrations in 4 cases were 120 +/- 28.7 micrograms/g 3 h after i.v. injection of 2 g cefazedone. The simultaneous serum levels were between 14.85 and 68.2 micrograms/ml, in one patient with extreme venous stasis the tissue concentration was only 8.1 micrograms/g. Cefazedone should be regarded as an antibiotic with excellent penetration into tissues.     

Pharmacokinetics and excretion of phenol red in the channel catfish.

1. Disposition of phenol red was examined in channel catfish (Ictalurus punctatus) after oral or intravascular (i.v.) dosing at 10 mg/kg body weight. 2. Phenol red was not detectable in plasma, urine, or bile after oral administration. 3. After i.v. dosing, plasma concentrations of phenol red were best described by a two-compartment pharmacokinetic model with distribution and elimination half-lives of 2.3 and 21 min, respectively. The apparent volume of distribution at steady state (Vss) was 225 ml/kg and total body clearance (Clb) was 658 ml/h per kg. Plasma protein binding was 19%. 4. Biliary excretion was the primary route of elimination of phenol red; in 24 h, 55% of the i.v. dose was excreted in bile compared with 24% in urine. No metabolites were detected in these fluids. 5. The use of anaesthesia during dosing had no effect on the quantitative excretion of phenol red by renal or biliary routes.     

Studies on toxicity and pharmacokinetics of the synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile.

The tripeptide-type synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile (1) was studied with respect to its toxicity and pharmacokinetics in mice, rats and rabbits. In mice the LD50 after i.v. injection was determined to be about 30-40 mg/kg. After i.v. injection and infusion in rats 1 caused a decrease in blood pressure up to 70-80% of initial values. The dose of 2 mg/kg.min led to a final outcome after about 15 min accompanied by a sharp decrease in blood pressure. The bleeding time after standardized incision of the rat tail was not significantly prolonged at doses which were tolerated. In pharmacokinetic studies the biologic half-life of 1 after i.v. injection was estimated to be about 12 min. After s.c. injection measurable plasma levels were obtained up to 5 h. Oral or intraduodenal administration of high doses of the inhibitor did not give effective plasma levels. Biliary excretion seems to be an important route of elimination. Cumulative excretion of 1 with the bile amounted to 31% of the dose within 240 min.     

In vivo toxicity, pharmacokinetic features and tissue distribution of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase

N-[2-(2,5-Dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236, CAS 233271-65-3) possesses potent anti-viral activity against zidovudine-sensitive as well as multidrug-resistant HIV-1 (human immunodeficiency virus) strains. The purpose of the present study was to examine in vivo toxicity, pharmacokinetic features and tissue distribution of HI-236 in mice. HI-236 had an elimination half-life of 85.8 min after i.v. administration and 86.6 min after i.p. administration. The systemic clearance of HI-236 was 4337 ml/h/kg after i.v. administration and 10,130 ml/h/kg after i.p. administration. Following i.v. injection, HI-236 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in lung, adipose tissue, skin, urinary bladder, adrenal gland and uterus + ovary. The concentration of HI-236 in brain tissue was comparable to that in the plasma, indicating that HI-236 easily crosses the blood-brain barrier. Following i.p. injection, HI-236 was rapidly absorbed with a tmax values of 5.6 min and showed linear pharmacokinetics within the dose range of 10-80 mg/kg. Following oral administration, HI-236 was absorbed with a tmax of 5.8 min. The intraperitoneal bioavailability was estimated at 42.9%, while the oral bioavailability was only 2.2%. The pharmacokinetic study described herein provides the basis for advanced pharmacodynamic study of HI-236.     

Kinetics and disposition of hexarelin, a peptidic growth hormone secretagogue, in rats.

To document the disposition of hexarelin, a peptidyl growth hormone secretagogue, male Sprague-Dawley rats received a 5-microg/kg bolus i.v. dose or three single s.c. doses of 5, 10, and 50 microg/kg. To assess hexarelin tissue distribution and excretion, rats were given 1 microg/kg of [(3)H]hexarelin (9.4 Ci/mmol). Metabolism of [(3)H]hexarelin was assessed in bile duct-exteriorized rats given 50 microg/kg where radiolabeled hexarelin biliary and urinary excretion was quantified. After its i.v. injection, hexarelin displayed a half-life of 75.9 +/- 9.3 min, a systemic clearance of 7.6 +/- 0.7 ml/min/kg, and a volume of distribution at steady state of 744 +/- 81 ml/kg. After s.c. administration, the area under the curve (477-3826 pmol.min/ml) estimated with increasing doses confirmed the absence of hexarelin accumulation. Clearance/F (12-15 ml/min/kg) and volume of distribution/F (1208-1222 ml/kg) were dose independent. Hexarelin bioavailability given s.c. was 64%. The highest radioactivity levels were detected in the kidney, liver, and duodenum. The pattern of hexarelin excretion was similar after i.v. or s.c. administrations. Total radioactivity in bile, urine, and feces corresponded to 60, 22, and 10% of the dose, respectively. Of the radioactivity excreted in bile and urine, 90 and 71% was unchanged hexarelin, respectively. These results suggest that: 1) the kinetics of hexarelin appear to be first order up to 50 microg/kg; 2) hexarelin is rapidly absorbed after s.c. administration; 3) biliary excretion is the primary route of hexarelin elimination; and 4) the high recovery of unchanged peptide in bile and urine demonstrates hexarelin stability toward proteolytic enzymes.     

Pharmacokinetics of guanosine in rats following intravenous or intramuscular administration of a 1:1 mixture of guanosine and acriflavine, a potential antitumor agent

A 1:1 mixture of acriflavine (ACF; CAS 8063-24-9) and guanosine is under evaluation in preclinical studies as a possible antitumor agent. Guanosine is known to potentiate the anti-cancer activity of ACF. We therefore investigated the pharmacokinetics of guanosine following administration of the ACF/guanosine mixture in rats. Rats were given guanosine (1 or 5 mg/kg) or ACF/guanosine (2 or 10 mg/kg) by i.v. bolus; or guanosine (3 or 15 mg/kg) or ACF/guanosine (6 or 30 mg/kg) by i.m. injection. We found that guanosine was rapidly cleared from the blood and transferred to tissues after i.m. administration of ACF/guanosine. The mean plasma half-lives (t_1/2) at the α and β phases were 0.091 and 6.86 h, or 0.09 and 7.51 h at a dose of 1 or 5 mg/kg guanosine, respectively. ACF had no effect on the plasma disappearance of guanosine following either i.v. bolus or i.m. administration of the combination mixture. Moreover, the ACF combination with guanosine did not significantly alter the values of MRT, V_dss, and CL_t of guanosine. Guanosine exhibited linear pharmacokinetics over the dose range from 1 to 5 mg/kg for i.v. doses and 3 to 15 mg/kg for i.m. doses. The bioavailability of guanosine after i.m. administration was 84% for 3 mg/kg dose and 88% for 15 mg/kg dose. ACF had no effects on biliary and urinary excretion of guanosine after i.m. administration. The cumulative amount of guanosine in urine after i.m. administration was about 5-fold larger than that in bile, indicating that guanosine is mostly excreted into the urine. Guanosine was widely distributed in all tissues examined in this study, but was most highly concentrated in the kidney after i.m. administration, followed by slow excretion to bile or urine. ACF had no effect on the tissue distribution of guanosine following i.m. administration. These characterizations of the pharmacokinetics of guanosine after administration of the ACF/guanosine combination will be useful in providing preclinical and clinical bases for the potential application of this combination to the treatment of cancer.     

Pharmacokinetics of glucosamine in the dog and in man

The pharmacokinetics, organ distribution, metabolism and excretion of glucosamine were studied in the dog giving uniformly labelled [14C]-glucosamine (sulfate), i.v. or orally, in single doses. Immediately after i.v. administration, the radioactivity in plasma is due to glucosamine, and freely diffuses into organs and tissues. This radioactivity disappears quickly from plasma (initial t1/2 = 13 min, terminal t1/2 = 118 min). After 30-60 min the radioactivity in plasma is no longer due to glucosamine, but is incorporated into alpha- and beta-globulins. The protein-incorporated radioactivity is found already 20-30 min after i.v. administration, reaches a peak after 8 h and then slowly disappears, with a t1/2 = 2.9 days. Of the administered radioactivity, more than 34% is excreted in the urine, mainly as glucosamine, and 1.7% is excreted in the feces. Radioactivity is excreted also as [14C]-CO2 in the expired air. The radioactivity, after i.v. administration, diffuses rapidly from blood into the body. Some organs show an active uptake of radioactivity, e.g. the liver and the kidney. Other tissues, such as the articular cartilage, also have an active uptake. In most other organs the radioactivity found can be explained by passive diffusion processes from plasma. After oral administration of a single dose of [14C]-glucosamine the radioactivity is quickly and almost completely absorbed from the gastrointestinal tract. The pattern of disappearance, metabolic transformation, tissue distribution and excretion of the radioactivity are consistent with those found after i.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of the new local anaesthetic N-[2-(2-Heptyloxyphenylcarbamoyloxy)ethyl]piperidinium chloride in rats and mice

Pharmacokinetics of a local anaesthetic of the carbanilate type (Heptacaine; in the following briefly called HCP), was studied using a labelled product, N-[2-(2-[1-14C]-heptyloxyphenylcarbamoyloxy)ethyl]piperidinum++ + chloride. Determination of HCP in biological material was based on double extraction of HCP from alkaline media into n-heptane. The plasma concentration of HCP following i.v. administration to rats was approximated by a biexponential function. An open two-compartment pharmacokinetic model was conferred to the data. The model parameter estimates are as follows: terminal elimination half-life 3.80 +/- 0.15 h, distribution volume at steady state 9.31 l/kg, total body clearance 73.4 ml/min/kg, mean residence time 2.1 h. The systemic availability of the orally given HCP in solution was 35.8%. The HCP plasma AUC vs. dose relationship was linear within doses ranging from 2.78 to 4.33 mg/kg. The brain uptake index of HCP in comparison with 3H2O was 62.2%. Autoradiography in mice injected i.v. showed a heterogeneous distribution of the label in the tissues and its excretion by the urinary and biliary pathways. HCP showed strong affinity to the lung tissue. During 96 h after i.v. administration, 21% and 62% of the 14C dose was excreted into urine and faeces, respectively, and after oral administration, the excretion was 17% and 43%, respectively.     

Absorption, distribution and excretion of zenarestat, a new aldose reductase inhibitor, in rats and dogs.

1. The absorption, distribution and excretion of zenarestat have been studied in male rats and dogs after i.v. and oral administration of 14C-zenarestat. 2. The bioavailability of zenarestat was 93% in rats and 65% in dogs. A major proportion of the plasma 14C in rats and dogs was due to unchanged drug. The terminal elimination half-life of zenarestat in plasma was 6 h in rats and dogs. 3. Except for organs associated with absorption and elimination, tissue 14C levels were lower than plasma levels in rats. The distribution to, and elimination from sciatic nerve were slower than those of other tissues. 4. Most of the 14C from 14C-zenarestat administered orally and i.v. to rats and dogs was excreted in the faeces. After i.v. dosing to bile duct-cannulated rats, 96% of the radioactive dose was excreted in the bile.     

Biliary excretion of hexachloro-1,3-butadiene and its relevance to tissue uptake and renal excretion in male rats.

Renal, biliary, pulmonary and faecal excretion experiments were carried out with labelled hexachloro-1,3-butadiene [( 14C]HCBD) in male Sprague-Dawley rats, given orally (p.o.) and intravenously (i.v.) in doses of 1 and 100 mg kg-1 as a solution in polyethylene glycol. The radioactivity excreted over 72 h was determined in rats fitted with exteriorized biliary cannulae and in rats whose bile ducts remained fully functional, respectively. In addition, bile duct-duodenum cannula-linked rats, of which the donor was given 100 mg kg-1 [14C]HCBD orally and the recipient had also a bile fistula, were examined within 30 h for radioactivity in the excreta, the kidney, the liver and the plasma. In non-cannulated rats, fractional urinary excretion decreased when the dosage increased and amounted to 23% and 8.6% after i.v. injection or 18.5% and 8.9% after p.o. administration of 1 and 100 mg kg-1, respectively. Pulmonary excretion of radioactivity was less than 9% and was not affected by the increase in dosage. In bile duct-cannulated rats, fractional urinary excretions were similar irrespective of the dose and the route of administration and amounted to ca. 7.5% of the dose. Decrease in fractional biliary excretion occurred with increase in dosage (88.7% vs 72%) after i.v. injection and (66.8% vs 58%) after gavage. In cannulated rats, faecal excretion was less than 0.5% after i.v. injection and accounted for 3% and 16% of the dose after p.o. administration of 1 and 100 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recombinant human parathyroid hormone 1-34: pharmacokinetics, tissue distribution and excretion in rats

The objective of this work was to characterize the preclinical pharmacokinetics, tissue distribution, and excretion profiles of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] in healthy rats. Pharmacokinetic properties of (125)I-rhPTH (1-34) were examined after a single subcutaneous (s.c.) and intravenous (i.v.) bolus injection, respectively. Tissue distribution and urinary, fecal, and biliary excretion patterns of (125)I-rhPTH (1-34) were also investigated following a single s.c. injection. Our results suggested that rhPTH (1-34) was rapidly distributed and cleared in a bi-exponential manner after a single i.v. bolus injection. Following a single s.c. administration, rhPTH (1-34) exhibited rapid and considerable absorption and declined in a mono-exponential manner, with the absolute bioavailability and elimination half-life of 65% and 3.4-4.1h, respectively. The TCA-precipitated radioactivity was widely distributed and rapidly diminished in most tissues/organs. Approximately 91% and 2% of the total radioactivity was recovered in urine and feces by 72h postdosing, respectively; whereas 6% excreted into bile up to 24h postdosing. These findings indicated high absolute bioavailability, rapid absorption and disposition of rhPTH (1-34) following a single s.c. administration in healthy rats. The accumulation of rhPTH (1-34) in tissues/organs examined appeared to be low. The major elimination route was urinary excretion.     

Pharmacokinetics,tissue distribution,metabolism, and excretion of ginsenoside Rg<Subscript>1</Subscript> in rats

The pharmacokinetics, tissue distribution, metabolism, and excretion of ginsenosides Rg₁ were studied in Wistar rats, by measuring the concentrations of Rg₁ and its metabolites in the blood, tissues, bile, urine, and feces after dosing. After intravenous (i.v.) administration, the elimination half-lives of Rg₁ and its metabolites were 1.82, 5.87, and 6.87 h, and the area under the curves were 1595.7, 597.5, and 805.6 ng· h/mL, respectively. After oral administration, the elimination half-lives of Rg₁ and its metabolites were 2.25, 6.73, 5.44, and 5.06 h, and the area under the curves were 2363.5, 4185.5, 3774.3, and 396.2 ng· h/mL, respectively. After i.v. administration, Rg₁ and its metabolites were well distributed to the tissues analyzed except for the brain. The maximum concentration of Rg₁ was reached in all tissues at 5 min post dose, and it was eliminated from most of the tissues except for the kidney faster than it was eliminated from the blood. The maximum concentration of the metabolites was reached in all tissues between 4 and 6 h post dose. After i.v. administration, the recovery of the Rg₁ prototype in the urine and bile was 27.96% and 60.77%, respectively. The metabolism of Rg₁ in the intestine was via a hydrolization pathway, with the 6- and 20-glucoside bond hydrolyzed gradually under the catalysis of β-glucosaccharase, and then the metabolites were reabsorbed into the blood. Finally, the total recovery of the Rg₁ prototype and its metabolites in the urine and feces were 51.31% and 47.46%, respectively.     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 1st communication: absorption, distribution and excretion in the mouse, rat and rabbit

Absorption, distribution and excretion of [3H]-enprostil ((+-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorpr osta -4,5,13(t)-trienoic acid methyl ester, TA-84135), a new anti-ulcer prostaglandin, were studied in mice, rats and rabbits. Radioactivity associated with enprostil was rapidly absorbed from the gastrointestinal tract with Tmax values of 15 or 30 min. Absorption was also efficient inasmuch as approximately 80% of an oral dose was recovered in bile and urine in 24 h in bile duct-cannulated rats. Experiments in pylorus-ligated, bile duct-cannulated rats demonstrated that enprostil was mainly absorbed from the intestine, rather than from the stomach. In mice given oral doses of 2, 8 and 32 micrograms/kg, Cmax and AUC values of enprostil radioequivalents increased proportionately to the increase in dose, indicating linear kinetics over this dose range. Distribution of enprostil-associated radioactivity was investigated in rats by quantitating tritium in various tissues after the oral administration of [3H]-enprostil. Radioactivity in tissues was highest at 15 or 30 min after dosing. Highest levels of radioactivity were found in the stomach and intestines, the organs which came into direct contact with the dose, and the liver and kidney, the organs involved in excretion of enprostil. The rate of elimination of enprostil-associated radioactivity from all tissues and from plasma was similar. Enprostil-associated radioactivity did not accumulate in any tissue. Radioactivity was found in fetuses following oral administration of [3H]-enprostil to rats on the 12th or 19th day of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)