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PubMed2005

Muscle endopin 1, a muscle intracellular serpin which strongly inhibits elastase: purification, characterization, cellular localization and tissue distribution.

In the present work, an endopin-like elastase inhibitor was purified for the first time from bovine muscle. A three-step chromatography procedure was developed including successively SP-Sepharose, Q-Sepharose and EMD-DEAE 650. This procedure provides about 300 microg of highly pure inhibitor from 500 g of bovine diaphragm muscle. The N-terminal sequence of the muscle elastase inhibitor, together with the sequence of a trypsin-generated peptide, showed 100% similarity with the cDNA deduced sequence of chromaffin cell endopin 1. Hence, the muscle inhibitor was designated muscle endopin 1 (mEndopin 1). mEndopin 1 had a molecular mass of 70 kDa, as assessed by both gel filtration and SDS/PAGE. According to the association rates determined, mEndopin 1 is a potent inhibitor of elastase (kass=2.41x10(7) M(-1).s(-1)) and trypsin (kass=3.92x10(6) M(-1).s(-1)), whereas plasmin (kass=1.78x10(3) M(-1).s(-1)) and chymotrypsin (kass=1.0x10(2) M(-1).s(-1)) were only moderately inhibited. By contrast, no inhibition was detected against several other selected serine proteinases, as well as against cysteine proteinases of the papain family. The cellular location of mEndopin in muscle tissue and its tissue distribution were investigated using a highly specific rabbit antiserum. The results obtained demonstrate an intracellular location and a wide distribution in bovine tissues.

Amino Acid Sequence↗

PubMed2006

AI-700 pharmacokinetics, tissue distribution and exhaled elimination kinetics in rats.

The purpose of these studies was to determine the pharmacokinetics, tissue distribution, and exhaled elimination kinetics in rats for intravenously administered AI-700, which consists of porous microspheres containing decafluorobutane (DFB), for use as an ultrasound contrast agent. [Pd]-AI-700 was administered intravenously to rats (10 mg microspheres/kg). Blood and tissue samples collected at specified times were analyzed for palladium by inductively coupled plasma-mass spectrometry (ICP-MS). AI-700 was also administered intravenously to rats (40 mg microspheres/kg) and expired air was collected over time. Expired air samples were analyzed for DFB by validated adsorbent trapping-thermal desorption-gas chromatography-mass spectrometry methodology. Pd from [Pd]-AI-700 was cleared from blood with a ca. 50-85% decline from peak concentration within 5 min. At 1440 min post-dose, 52-72% of the Pd dose was recovered from organs of the reticuloendothelial system. Approximately 77% of the intravenously injected DFB was found in expired air within 3h after dosing, with most of the DFB dose (61+/-6%) expired within the first 10 min after dosing. As expected, the microspheres were cleared through the reticuloendothelial system, and the DFB was eliminated in expired air, with more than half of the DFB eliminated within the first 10 min after dosing.

Air↗

PubMed1988

Effect of high dose alpha-tocopherol acetate on the toxicity and tissue distribution of adriamycin (doxorubicin).

The effect of alpha-tocopherol acetate (VE) on the toxicity and tissue distribution of adriamycin (ADM) in mice was studied. After the administration of ADM in 2 doses of 15 mg/kg, mice pretreated with olive oil survived 7.1 +/- 1.0 days, while mice pretreated with VE in ten doses of 500 mg/kg/day (subcutaneously) survived 5.5 +/- 1.7 days (p less than 0.01). The total concentration of ADM and its major metabolite, aglycone I in the liver (1, 3, 5 h), kidneys (1, 3 h), and heart (3 h), as determined by high performance liquid chromatography was significantly higher in the VE-pretreated group (four doses of 500 mg/kg/day) than in the olive oil-pretreated group. The aglycone levels of the VE-pretreated group were significantly higher than those of the olive oil-pretreated group in the liver, kidney and heart, but there was no significant difference between the groups in the levels of the unmetabolized form. Considering these results, the administration of VE concomitant with anti-tumor drugs, including ADM, requires great caution.

Animals↗

PubMed1987

Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog.

The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Pharmacokinetics, tissue distribution and placental permeability of tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (a retinoidal benzoic acid derivative) in hamsters.

Tritiated tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (TTNPB; Ro 13-7410) was administered as a single oral bolus to pregnant hamsters (day 8) to determine the maternal plasma pharmacokinetic profile and peripheral tissue distribution patterns. Blood and tissue, including embryo or fetus, were collected at specific time intervals to 96 h and assayed for total radioactive compounds and/or parent retinoid. No lag time was required to describe retinoid absorption (t 1/2 pi = 1.2 h) with peak plasma levels at 2.4 h; the concentrations then declined with exponential elimination from the central compartment (t 1/2 e = 3 h). The maximum concentrations of circulating radioactive compound or metabolites after 100 micrograms/kg [3H]2-TTNPB occurred in liver greater than fetus greater than adrenal greater than lung approximately equal to kidney greater than plasma; after 1000 micrograms/kg, maternal liver accumulated the highest concentration followed by plasma greater than fetus = placenta = uterus. An unidentified, polar metabolite was detected in plasma at 0.5 h and by 12 h constituted greater than 90% of the total circulating radioactivity. TTNPB was absorbed and cleared more slowly, concentrated in the conceptus to a higher degree and possessed greater intrinsic activity than the naturally-occurring tetraene retinoids. These properties contribute to the marked teratogenic activity of TTNPB as compared to the tetraene retinoids.

Animals↗

PubMed1989

Clearance kinetics and tissue distribution of aggregated human serum IgA in rats.

In the present study the clearance kinetics and tissue distribution of human polyclonal heat-aggregated serum IgA (AIgA) of different sizes in rats was studied after intravenous administration of 125I-AIgA. The 125I-AIgA of different sizes disappeared from the circulation in a biphasic manner with an initial rapid half-life (T1/2) and a second slower T1/2. The first T1/2 was related to the size of the 125I-AIgA: high molecular weight (MW) 125I-AIgA was cleared much faster than 125I-AIgA with a low MW. Relatively more degradation products were observed in blood when high MW 125I-AIgA were injected as compared to low MW 125I-AIgA. The AIgA were mainly taken up by the liver. Eight minutes after injection of high MW 125I-AIgA, 90% of the injected dose was found in the liver, whereas less than 2% was detected in the spleen. Very little activity was detectable in other organs, such as lungs, heart and kidneys. In the present study 1-3% of the injected 125I-AIgA were found in the bile. Analysis of this material revealed that low MW 125I-AIgA were transported more efficiently to the bile than high MW 125I-AIgA. To obtain more insight into the receptors involved in the clearance of 125I-AIgA, rats were pretreated with ovalbumin or asialofetuin. The clearance of 125I-AIgA of different sizes was inhibited when rats were pretreated with asialofetuin. Pretreatment with ovalbumin had no effect on the clearance rates of 125I-AIgA. These results suggest a role for carbohydrate receptors, which recognize glycoprotein-containing galactose terminal residues on Kupffer cells, in the clearance of 125I-AIgA.

Animals↗

PubMed1994

Comparison of quantitative whole-body autoradiographic and tissue dissection techniques in the evaluation of the tissue distribution of [14C]daptomycin in rats.

Quantitative whole-body autoradiography (QWBA) was evaluated and compared to tissue dissection/liquid scintillation counting (TD/LSC) techniques by determining the tissue distribution of radiocarbon in rats following iv administration of the antibiotic [14C]daptomycin (LY146032). QWBA, using computer-assisted video-image analysis, was initially evaluated by characterizing and calibrating commercial standards to blood and brain, kidney, liver, and lung homogenates. Frozen (carboxymethyl)cellulose blocks containing tissue homogenates spiked with [14C]glucose (370-37,000 Bq/g or 10-1000 nCi/g) were sectioned and optical densities (OD) measured. Characterization of QWBA included repeated measures data analysis to determine the significance of tissue type and intra- and inter-section and block variability. Regression models relating OD to radiocarbon concentration were also used to calibrate commercial standards for use in QWBA analyses. Results indicated that there were no substantial differences between OD readings from different tissues; however, the greatest source of variation in OD reading was section thickness. Because quantitative variations were largely attributed to section thickness, an internal standard (IS), consisting of liver homogenates spiked with [14C]glucose, was evaluated as a correction factor. Tissue concentrations of radiocarbon in male Fischer 344 rats were evaluated by QWBA and TD/LSC techniques 0.25 h following a single iv 10 mg/kg dose of [14C]daptomycin. Results indicated that tissue concentrations of radiocarbon obtained by QWBA, normalized using an IS, were comparable to those obtained by TD/LSC.

Amino Acid Sequence↗

PubMed1981

Comparative tissue distribution of ceforanide, cefazolin, and cefamandole in rats.

The comparative tissue distribution of ceforanide, cefazolin, and cefamandole was determined in rats after subcutaneous doses of 100 mg/kg. Ceforanide had the longest plasma half-life, 0.9 h, versus 0.5 h for cefazolin and 0.4 h for cefamandole, and the highest area under the plasma concentration time curve, 324 micrograms x h per ml, versus 184 micrograms x h per ml for cefazolin and 42 micrograms x h per ml for cefamandole. The peak plasma concentrations of ceforanide and cefazolin were 173 and 140 micrograms/ml, respectively, and were threefold higher than that of cefamandole (49 micrograms/ml). Measureable concentrations of the three compounds were found in the liver, kidneys, lungs, submaxillary glands, cervical lymph nodes, bones, heart, abdominal muscles, eyes, and testes, with cefamandole levels being generally lower and more variable. The peak tissue levels of ceforanide and cefazolin were comparable, within the limit of data variation, and were considerably higher than that of cefamandole. The tissue half-lives of these cephalosporins were similar to the respective plasma half-lives.

Animals↗

PubMed1990

Excretion, metabolism and tissue distribution of a spin trapping agent, alpha-phenyl-N-tert-butyl-nitrone (PBN) in rats.

The objective of this study is using radiolabelled PBN to determine the tissue distribution, excretion, and metabolism of PBN in rats in order to evaluate the effective time to trap free radical in appropriate tissue(s). Our results demonstrated that PBN is rapidly absorbed when it is injected intraperitoneally in the animal. PBN can be used as an effective spin trapping agent for a variety of tissues since it is evenly distributed among a wide range of tissues measured. Since there is no difference in the tissue concentrations and distribution pattern of PBN at 15, 30 and 60 min after injection of PBN, it is appropriate to choose any of these time intervals to terminate the experiment and extract the spin adduct. The excretion of PBN, however, is slow. The majority of the radioactivity (70%) was excreted by the first 3 days. Only 5.7% of radioactivity was collected from 3 to 14 days. The remaining 25% of the radioactivity may be in the form of expired 14CO2. Trace amounts of radioactivity were recovered in the feces. PBN has probably only one major form of metabolite excreted in the urine. A small amount of the parent compound, however, was also excreted in the urine. The chemical structure of the metabolite(s) is still unknown.

Animals↗

PubMed2003

Absorption, tissue distribution, excretion, and metabolism of clothianidin in rats.

Absorption, distribution, excretion, and metabolism of clothianidin [(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine] were investigated after a single oral administration of [nitroimino-(14)C]- or [thiazolyl-2-(14)C]clothianidin to male and female rats at a dose of 5 mg/kg of body weight (bw) (low dose) or 250 mg/kg of bw (high dose). The maximum concentration of carbon-14 in blood occurred 2 h after administration of the low oral dose for both labeled clothianidins, and then the concentration of carbon-14 in blood decreased with a half-life of 2.9-4.0 h. The orally administered carbon-14 was rapidly and extensively distributed to all tissues and organs within 2 h after administration, especially to the kidney and liver, but was rapidly and almost completely eliminated from all tissues and organs with no evidence of accumulation. The orally administered carbon-14 was almost completely excreted into urine and feces within 2 days after administration, and approximately 90% of the administered dose was excreted via urine. The major compound in excreta was clothianidin, accounting for >60% of the administered dose. The major metabolic reactions of clothianidin in rats were oxidative demethylation to form N-(2-chlorothiazol-5-ylmethyl)-N'-nitroguanidine and the cleavage of the carbon-nitrogen bond between the thiazolylmethyl moiety and the nitroguanidine moiety. The part of the molecule containing the nitroguanidine moiety was transformed mainly to N-methyl-N'-nitroguanidine, whereas the thiazol moiety was further metabolized to 2-(methylthio)thiazole-5-carboxylic acid. With the exception of the transiently delayed excretion of carbon-14 at the high-dose level, the rates of biokinetics, excretion, distribution, and metabolism of clothianidin were not markedly influenced by dose level and sex.

Animals↗

PubMed1980

Age-associated changes in tissue distribution and uptake of 3H-digoxin in mice and guinea pigs.

The influence of age on tissue distribution of digoxin in mice and guinea pigs and uptake by mouse heart slices was investigated. 4 h after a single dose of 3 H-digoxin, tissue:plasma ratios were significantly greater in very young animals and declined with increasing age. A similar relationship was apparent for packed red blood cell:plasma concentration ratios in mice. Uptake of 3H-digoxin by heart tissue slices was also higher for 21-day-old mice than 200-day-old mice. These data seem to correlate with the larger volume of distribution of digoxin observed in the young. Tissue digoxin relative to plasma concentration seems higher in the young, although they appear less sensitive to the effects of cardiac glycosides.

Aging↗

PubMed1999

Comparative studies on tissue distributions of organophosphorus, carbamate and organochlorine pesticides in decedents intoxicated with these chemicals.

This paper describes the tissue distributions of dichlorvos, an organophosphate, chlorpyrifos-methyl, an organophosphorothioate, methomyl, a carbamate, and endrin, an organochlorine, in three individuals (Cases 1-3) who died after ingesting insecticidal preparations containing these chemicals. In Case 1 involving dichlorvos and chlorpyrifos-methyl, no dichlorvos was detected in most of the blood and tissue samples. Tiny amounts of dichlorvos (0.067 mg/L and 0.027 mg/L) were detected in the vitreous humor and cerebrospinal fluid, respectively. The chlorpyrifos-methyl concentrations in the blood samples were very site-dependent with a range of 0.615-2.24 mg/L. The tissue concentrations of chlorpyrifos-methyl were within the range 0.379-8.60 mg/kg. The total amounts of dichlorvos and chlorpyrifos-methyl in the stomach were 879 and 612 mg, respectively. The serum cholinesterase activity was 3 IU/L/37 degrees C. In Case 2 involving methomyl, the methomyl concentrations in the blood samples were very site-dependent with a range of 0.56-4.75 mg/L. The tissue concentrations of methomyl were 2.61 mg/kg or less, no methomyl being detected in the spleen, liver and kidney. The methomyl concentrations in the cerebrospinal fluid and vitreous humor were 5.37 and 4.75 mg/L, respectively. The stomach contained 85 mg methomyl. The serum cholinesterase activity was 73 IU/L/37 degrees C. In Case 3 involving endrin, the victim underwent medical treatment for 7 h after ingesting an endrin preparation. The differences in the endrin concentrations among the blood samples were small, with a range of 0.353-0.615 mg/L. The tissue concentrations of endrin were within the range 0.467-13.3 mg/kg. The endrin in the stomach (66 mg) was adsorbed almost completely on the activated charcoal that was administered for medical treatment.

Aged↗

PubMed1991

Effect of concurrent graft-versus-host reaction on tissue distribution and infectious titer of murine cytomegalovirus.

Infection with cytomegalovirus is a major concern following bone marrow transplantation. Previously, we have described a model whereby infection by MCMV concurrent with the injection of parental strain lymphoid cells into F1 recipient mice results in a severe graft-versus-host reaction (GvHR) when the donor and host differ at the class I MHC locus (i.e., class I MHC disparate GvHR). The present studies were performed to determine whether one consequence of this severe GvHR is the alteration of the tissue distribution and/or levels of infectious virus as compared to mice not undergoing GvHR. Using PCR to detect MCMV DNA, it was observed that the tissue distribution of virus 3 days after injection was identical in recipients of virus alone and of GvHR plus virus inocula. At two weeks post injection, virus was recovered from the salivary gland and pancreas in both groups. In contrast to recipients of MCMV alone, lung tissue from GvHR plus virus mice also contained viral DNA. Notably, these results were corroborated by the plaque assay. Moreover, salivary gland and pancreas from recipients of GvHR plus virus were found to contain higher titers of infectious virus. In total, the data demonstrate that, with the notable exception of the lung, the distribution of virus was not changed in the animals despite the presence of a concurrent severe GvHR. However, viral replication in infected tissues appeared less restricted in these recipients.

Animals↗

PubMed1998

Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic interactions.

The authors sought to determine the effect of concomitant peroral (PO) administration of cyclosporine (CsA) and sirolimus (SRL, rapamycin) on the tissue distributions of CsA and SRL in the rat. Groups of four adult male Wistar-Furth rats were treated for 14 days with 2.5, 5.0, or 10.0 mg CsA/kg x day. Other groups of four adult male Wistar-Furth rats were treated for 14 days with a 1-to-6.25 weight-to-weight ratio of SRL to CsA at SRL doses of 0.4, 0.8, or 1.6 mg/kg x day. Concentrations of CsA and SRL in homogenates of heart, intestinal, kidney, liver, lung, muscle, spleen, and testes were compared to those in whole blood (WB). There was a large, dose-dependent, distinctive distribution of CsA among rat tissues, as has previously been well documented. At a constant molar dose ratio, concomitant oral administration of SRL produced an approximately two-fold increase in the concentrations of CsA in rat tissues, although SRL did not change the CsA tissue-to-WB partition coefficients. Concomitant oral CsA administration produced dose-dependent increases in SRL tissue concentrations and decreases in the SRL tissue-to-WB partition coefficients. The increases in tissue and WB concentrations on coadministration of both agents may be explained either by an increase in absorption caused by competition between the two agents for binding sites on P-glycoprotein in the gut, a reduced rate of metabolism, or to an as yet unidentified elimination mechanism. The dose-independent and unchanged CsA tissue-to-WB partition coefficients suggest that SRL does not affect the equilibrium of CsA between the central and tissue compartments, namely the tissue uptake or intracellular binding. Altered values of the SRL tissue-to-WB partition coefficients suggest that, under the conditions studied, CsA disturbs the equilibrium of SRL between the central and tissue compartments.

Absorption↗

PubMed2000

[The effect of splenectomy on circulating endotoxin clearance and tissue distribution of endotoxin in rats].

OBJECTIVE: To study the effect of splenectomy on circulating endotoxin clearance and tissue distribution of endotoxin, and investigate the potential mechanism(s) underlying inflammatory response and multiple organ damage following splenectomy. METHODS: 112 male Wistar rats were randomly divided into two groups: control group (n = 56, included omentectomy and mobilization of the spleen), and splenectomy group (n = 56). The latter was further sub divided into 10-min, 0.5-, 1.5-, 4-, 12-, 24-hour groups after endotoxin challenge. Tissue and systemic blood endotoxin concentrations were measured using the chromogenic limulus amebocyte lysate (LAL), which was modified by perchloric acid (PCA) pretreatment for samples. Liver function parameter and lung tissue myeloperoxidase (MPO) were also measured. RESULTS: After endotoxin administration, plasma endotoxin concentrations were higher in splenectomized rats than in controls at 10 minutes and 0.5 hour (P < 0.01). Endotoxin clearance was delayed in liver and lung in animals after splenectomy. MPO values of the control group were significantly higher than those of splenectomy groups (P < 0.01). CONCLUSION: Splenectomy can lead to impairment of intravascular clearance of endotoxin and endotoxin accumulation in liver and lung. Endotoxin accumulated in local sites may be involved in the development of inflammatory response and multiple organ dysfunction following splenectomy.

Animals↗

PubMed2000

Photodynamic therapy efficacy and tissue distribution of hypericin in a mouse P388 lymphoma tumor model.

The phototherapeutic properties and tissue distribution of hypericin were investigated in DBA/2 mice bearing subcutaneously transplanted P388 lymphoma cells. The efficacy of the photodynamic therapy (PDT) 2 h after administration of hypericin (2, 5, or 20 mg/kg, i.p., 120 J/cm2, 595 nm) was substantially greater than the efficacy after a 24 h interval. PDT with Photofrin (5 mg/kg, i.p., 24-h interval, 120 J/cm2, 630 nm) showed no significant antitumoral effect. The hypericin uptake in some tissues was measured after administration of hypericin (5 or 20 mg/kg, i.p.) up to 168 h. A comparison of the distribution data and the PDT efficacy at various intervals suggests that the plasma concentration of hypericin, and to a lesser extent the tumor uptake, determines the tumor response to PDT with hypericin.

Animals↗

PubMed1989

The tissue distribution of microfibrils reacting with a monospecific antibody to MAGP, the major glycoprotein antigen of elastin-associated microfibrils.

Elastic tissue, when viewed in the electron microscope, consists of an amorphous component that is immunoreactive with anti-tropoelastin (TE) antibodies and microfibrils, that react with monospecific antibodies against a 31 kDa microfibrillar glycoprotein constituent, called MAGP. A detailed study of the tissue distribution of microfibrils and of the two elastic tissue antibodies has been carried out, using single and double-labeled immunogold techniques in high resolution electron microscopy. Microfibrils similar in appearance to those associated with elastic tissue and immunoreactive with the anti-MAGP antibody, have been demonstrated in many tissues in the absence of amorphous elastic tissue. In the majority of these tissues, specific anti-TE antibody localization was demonstrated in the immediate vicinity of the microfibrils, or alternatively, the microfibrils were shown to be in direct continuity with microfibrils of similar morphology, which were associated with material immunoreactive with anti-TE antibody. The diameter of these microfibrils varied between 8 nm and 16 nm. They were unbranched structures of indefinite length, with a tubular profile on cross section and periodic staining in longitudinal section. In some tissues, notably in the ciliary zonule and in the mesangial region of the renal glomerulus, microfibrils of similar morphology were demonstrated which were immunoreactive with anti-MAGP antibody, but which were unrelated to amorphous elastic tissue and with which anti-TE antibody localization could not be demonstrated. The evidence available supports the conclusion that all these microfibrils are members of a single class of structures, which are widely distributed in the tissues and which are secreted by a range of cell types. Attention is directed to the close relationship between these microfibrils and the basement membrane of the glomerulus, of uterine smooth muscle, of the basal cells of the epidermis and of the reticulum cells of the spleen.

Animals↗

PubMed2000

Pharmacokinetics and tissue distribution of ipriflavone, an isoflavone derivative, after intravenous administration to rabbits.

Pharmacokinetic parameters of ipriflavone and its main metabolites, M1 and M5, after intravenous administration of spray-dried ipriflavone, SIP (10, 20, and 30 mg/kg as ipriflavone) and tissue distribution of ipriflavone, M1, and M5 after intravenous administration of SIP (20 mg/kg as ipriflavone) were evaluated in rabbits. Saturable metabolism of ipriflavone were observed after intravenous administration; at an ipriflavone dose of 30 mg/kg, the dose-normalized (based on 10 mg/kg) AUC was significantly greater (72.4 and 64.0 versus 103 microg min/mL), Cl was significantly slower (138 and 156 versus 97.6 mL/min/kg), and terminal half-life (94.8 and 129 versus 211 min) and mean residence time (91.3 and 116 versus 186 min) were significantly longer than those at 10 and 20 mg/kg. The AUC of M1 was also significantly greater at ipriflavone dose of 30 mg/kg. The terminal half-life, AUC, and renal clearance of M5 were also significantly different at ipriflavone dose of 30 mg/kg than those at 10 and 20 mg/kg. Ipriflavone was widely distributed in most rabbit tissues studied and the tissue-to-plasma (T/P) ratios of ipriflavone were greater than unity in all tissues (or organs) studied except spleen, indicating that ipriflavone has high affinity to rabbit tissues studied, and this could be supported by considerably high values of the apparent volume of distribution of ipriflavone at steady state (11 400-16 900 mL/kg). M1 and M5 were also detected in most rabbit tissues with considerable amount of M1 (T/P ratio of 9.43) and M5 (T/P ratio of 4.66) in the kidney.

Analgesics↗