Pharmacokinetics of sulphadimethoxine in channel catfish (Ictalurus punctatus)

1. Plasma clearance, bioavailability, tissue disposition and elimination of 14C-sulphadimethoxine (SDM) were studied in channel catfish (Ictalurus punctatus) after intravenous (i.v.) and oral dosing (per os; p.o.) at 40 mg/kg body weight. 2. Analysis of blood SDM concentrations over time for intravascularly administered SDM showed that disposition and elimination were best described by a two-compartment pharmacokinetic model; estimated half-lives for SDM in blood were 0.09 and 12.6 h for the distribution and elimination phases, respectively. 3. SDM was found primarily in muscle tissue immediately after oral administration; however, clearance from muscle was rapid, with a half-life of 13.1 h. 4. With time, SDM-derived radioactivity became concentrated in the bile and was eliminated slowly (t 1/2 = 115.5 h). 5. Binding of SDM in channel catfish plasma was low (18%) and was non-specific and dose-independent. 6. With the exception of the initial, rapid clearance of SDM from blood, the pharmacokinetic parameters describing SDM distribution and elimination in channel catfish were similar to values reported for other vertebrate species; the rapid distribution of SDM from blood to the tissues in the catfish may be related to species differences in the plasma binding of SDM.     

Pharmacokinetics of sulphadimethoxine in channel catfish (Ictalurus punctatus)

1. Plasma clearance, bioavailability, tissue disposition and elimination of ¹⁴C-sulphadimethoxine (SDM) were studied in channel catfish (Ictalurus punctatus) after intravenous (i.v.) and oral dosing (per os; p.o.) at 40 mg/kg body weight.

2. Analysis of blood SDM concentrations over time for intravascularly administered SDM showed that disposition and elimination were best described by a two-compartment pharmacokinetic model; estimated half-lives for SDM in blood were 0.09 and 12.6 h for the distribution and elimination phases, respectively.

3. SDM was found primarily in muscle tissue immediately after oral administration; however, clearance from muscle was rapid, with a half-life of 13.1 h.

4. With time, SDM-derived radioactivity became concentrated in the bile and was eliminated slowly (t_1/2 = 115.5h).

5. Binding of SDM in channel catfish plasma was low (18%) and was non-specific and dose-independent.

6. With the exception of the initial, rapid clearance of SDM from blood, the pharmacokinetic parameters describing SDM distribution and elimination in channel catfish were similar to values reported for other vertebrate species; the rapid distribution of SDM from blood to the tissues in the catfish may be related to species differences in the plasma binding of SDM.     

Tissue disposition and excretion of 14C-labelled aflatoxin B1 after oral administration in channel catfish.

The pharmacokinetics, tissue distribution and excretion of ¹⁴C-labelled aflatoxin B₁ (AFB₁) were examined after oral administration (250 μg/kg body weight) in channel catfish (Ictalurus punctatus). Plasma concentrations of parent AFB₁ were best described by a one-compartment pharmacokinetic model, in which peak plasma concentration (503 ppb) occurred at 4.1 hr after dosing. The absorption and elimination half-lives were 1.5 and 3.7 hr, respectively. AFB₁ was highly bound (95%) to plasma proteins. Concentrations of ¹⁴C (in AFB₁ equivalents) measured in the tissues were highest at 4 hr, ranging from 596 ppb in the plasma to 40 ppb in the muscle. AFB₁ residues were rapidly depleted; at 24 hr the concentrations in the plasma and muscle were 32 and <5 ppb, respectively. Concentrations in the bile exceeded 2000 ppb (at 24 hr), whereas the highest concentration in the urine was 51 ppb (4–6-hr collection interval). Renal and biliary excretion accounted for <5% of the administered dose, indicating incomplete absorption. Pharmacokinetic modelling and tissue data demonstrate a very low potential for the accumulation of AFB₁ and its metabolites in the edible flesh of channel catfish through the consumption of AFB₁-contaminated feed.     

Bioavailability, metabolism, and renal excretion of benzoic acid in the channel catfish (Ictalurus punctatus)

The pharmacokinetics and metabolism of the model compound benzoic acid were examined after intravascular (iv) and po administration at 10 mg/kg in the channel catfish (Ictalurus punctatus). A two-compartment pharmacokinetic model best described the plasma disposition of parent benzoic acid after iv dosing. The following pharmacokinetic values were estimated: elimination half-life, 5.9 hr; total body clearance, 61 ml/hr/kg; and volume of distribution (steady-state), 369 ml/kg. Plasma protein binding of [14C]benzoic acid was 18%. Benzoic acid was rapidly and extensively absorbed after po administration; absorption half-life was 0.8 hr and bioavailability was 95%. Renal excretion was the primary route of elimination of benzoic acid and metabolites. More than 80% of the iv-administered 14C was recovered in the urine in 24 hr. Unchanged benzoic acid comprised more than 90% of the urinary radiolabel. The major urinary metabolite was benzoyltaurine, which comprised 6-7% of the excreted 14C. Channel catfish were qualitatively similar to other teleost fishes in the formation of the taurine conjugate of benzoic acid. In contrast, the primary mammalian metabolite is the glycine conjugate, hippuric acid.     

Pharmacokinetics, tissue distribution and excretion of vinflunine.

The plasma pharmacokinetics, tissue distribution, excretion and binding to plasma proteins of vinflunine, were investigated after intravenous (iv) administration. We obtained plasma profiles after iv administration of vinflunine at the doses of 3.5, 7 and 14 mg/kg in rats. The t1/2 values for vinflunine were estimated to be 18.38+/-1.20, 17.05+/-0.77, 18.35+/-1.57 h, and the mean AUC0-t values were 3.48+/-0.38, 6.54+/-0.68, 12.79+/-2.93 microg x h/ml, respectively. Of the various tissues tested, vinflunine was widely distributed into tissues, with the highest concentrations of vinflunine being found in well perfused organs. Maximal concentration of vinflunine was reached at 0.5 h postdose in the majority of tissues. In tumor-bearing mice, the similar pattern of tissue distribution was observable, except that vinflunine can be distributed into tumor. The binding of vinflunine in human and rat plasma proteins were 39.6% and 58.4% respectively. Within 96 h after administration, 9.58%, 15.36% and 0.71% of the given dose was excreted in urine, feces and bile, respectively. In conclusion, Vinflunine had a longer terminal half-life, a wide tissue distribution and less than 25% of the given dose was excreted as unchanged drug, suggesting metabolism as a major style of elimination.     

Excretion of phenol red and its glucuronide in the dogfish shark.

1. The biliary and urinary excretion of phenol red and its glucuronide was measured in dogfish sharks, Squalus acanthias, in both intact animals and animals with biliary fistula. 2. Phenol red is extensively metabolized to its glucuronide by the dogfish shark and both forms of the compound are actively transported into bile and urine. 3. Both compounds are transferred from plasma to urine and bile against a large concentration gradient; the transfer process is saturable most easily in the renal compartment but also in the hepatic compartment; and both excretion routes for the free drug and the glucuronide are inhibited by probenecid. 4. There were no significant differences in the 48 h biliary excretion of total (free + glucuronide) phenol red, but the urine or intact fish contained two-fold more total drug than did animals with fistulae.     

Tissue disposition and excretion of C-labelled aflatoxin B1 after oral administration in channel catfish

The pharmacokinetics, tissue distribution and excretion of ¹⁴C-labelled aflatoxin B₁ (AFB₁) were examined after oral administration (250 μg/kg body weight) in channel catfish (Ictalurus punctatus). Plasma concentrations of parent AFB₁ were best described by a one-compartment pharmacokinetic model, in which peak plasma concentration (503 ppb) occurred at 4.1 hr after dosing. The absorption and elimination half-lives were 1.5 and 3.7 hr, respectively. AFB₁ was highly bound (95%) to plasma proteins. Concentrations of ¹⁴C (in AFB₁ equivalents) measured in the tissues were highest at 4 hr, ranging from 596 ppb in the plasma to 40 ppb in the muscle. AFB₁ residues were rapidly depleted; at 24 hr the concentrations in the plasma and muscle were 32 and <5 ppb, respectively. Concentrations in the bile exceeded 2000 ppb (at 24 hr), whereas the highest concentration in the urine was 51 ppb (4–6-hr collection interval). Renal and biliary excretion accounted for <5% of the administered dose, indicating incomplete absorption. Pharmacokinetic modelling and tissue data demonstrate a very low potential for the accumulation of AFB₁ and its metabolites in the edible flesh of channel catfish through the consumption of AFB₁-contaminated feed.     

Pharmacokinetics of phenol red in rat models of liver damage prepared by liver targeting of carbon tetrachloride

Animal models prepared by treatment with carbon tetrachloride (CCl(4)) have been used to examine drug disposition in hepatic disorder. However, previous studies demonstrated that systemic administration of CCl(4) impaired not only hepatic but also renal function. We recently reported that application of CCl(4) to the rat liver surface produced hepatic damage without impairing renal function. In the present study, we examined the pharmacokinetics of phenol red in our developed rat model. The rats treated with CCl(4) by liver surface application exhibited decreases in the biliary clearance of phenol red in comparison with normal rats from 0.54+/-0.03 to 0.31+/-0.06 ml/min, suggesting hepatic damage. In these rats, the renal clearance of phenol red did not decrease (0.50+/-0.16 ml/min vs. 0.46+/-0.07 ml/min in normal rats). On the other hand, oral and intraperitoneal treatments with CCl(4) reduced not only the biliary clearance of phenol red (0.34+/-0.03 ml/min in p.o. treated rats, 0.18+/-0.01 ml/min in i.p. treated rats) but also the renal clearance (0.26+/-0.05 ml/min in p.o. treated rats, 0.18+/-0.06 ml/min in i.p. treated rats) as compared with normal rats. These findings indicate that the rat model of liver damage prepared by liver surface application of CCl(4) is useful to investigate the effects of hepatic disorder on the pharmacokinetics of drugs.     

Pharmacokinetics of biliary excretion in man. VI. Indocyanine green

Summary The pharmacokinetics of Indocyanine Green (ICG) has been studied in 15 patients given 0.5, 1.0 and 2.0 mg · kg^–1. The plasma disappearance and biliary excretion rate were measured in patients with tightly fitting catheters under slight negative pressure in order to achieve complete collection of bile. Recovery of unchanged ICG in bile over 18 h after the i.v. injection was 80% of the dose in all three dose groups.Plasma disappearance in all 3 groups was biphasic, showing an initial phase with a t_1/2 of 3–4 min and a secondary phase with a dose-dependent apparent t_1/2 of 67.6, 72.5 and 88.7 min, respectively. After 0.5 and 1.0 mg · kg^–1 the biliary excretion rate curves showed an ascending phase with a mean t_1/2 of 5 min and a descending phase with a mean t_1/2 of 72 min. It was inferred that the secondary component of the plasma-decay mainly reflected the biliary excretion rate. After 2.0 mg · kg^–1 in some patients the biliary excretion curve showed features of saturation; the t_1/2 of the descending phase ranged from 73 to 440 min, and the time of maximal excretion was increased from 1.3 to 2.7 h after injection, whilst the mean maximal excretion rate was in the same range as the excretion rate after the 1.0 mg · kg^–1 dose. The non-linear pharmacokinetics was only moderately reflected in the measured plasma disappearance patterns. Two compartment analysis of the plasma levels indicated a clearance of 230–260 ml · min^–1, whereas the clearance conventionally calculated from the initial t_1/2 was 475 ml · min^–1. The volume of the central compartment in 70 kg patients was 2.31, which is about the plasma volume. The fictive volume of distribution in the liver (V₂) was 70–90 l, indicating marked hepatic storage of ICG. This was probably due to the very low liver-to-plasma transport rate (k₂₁) of 0.006–0.10 min^–1. Thus, the biliary excretion of ICG can be quantified by 2-compartment pharmacokinetic analysis of plasma disappearance curves, including a secondary phase. The latter, slow component was apparent at very low plasma levels due to the marked hepatic storage, and it was also influenced by retention of small amounts of impurities or degradation products. Improved detectability of this phase cannot simply be obtained by increasing the dose, since at doses exceeding 1.0 mg · kg^–1 non-linear elimination may complicate the pharmacokinetic analysis.     

Pharmacokinetics of arbekacin in dogs. I. Serum concentration and urinary excretion

A new aminoglycoside antibiotic, arbekacin (HBK) was intramuscularly and intravenously administered to dogs in order to study its pharmacokinetics in comparison to amikacin (AMK). The results obtained are summarized as follows. Serum concentrations of HBK were well correlated with dose levels. The dose-serum concentration relationship with HBK was similar to other aminoglycoside antibiotics. Biological half-lives of HBK and AMK were both about 1 hour in dogs. This was also similar to other aminoglycoside antibiotics. There was no significant difference in peak serum concentrations between 1 hour intravenous infusion and intramuscular injection of HBK at 2 mg/kg in dogs. Repetitive administration of HBK to dogs at 2 mg/kg twice a day for 14 days did not affect its serum concentration and biological half-life. Urinary excretion of HBK in dogs in 24 hours after administration accounted for about 80-90%.     

Pharmacokinetics and renal excretion of sulfamethoxazole in sheep

Pharmacokinetics and urinary excretion of sulfamethoxazole were investigated in healthy sheep. From the plasma disappearance curves after intravenous bolus injection (50 mg/kg), the half-life and volume of distribution were found to be 76±14 min and 0.41±0.18 lit/kg respectively. Body clearance was 4.06±1.03 ml/kg/min. Very low Concentration of drug was present in plasma after 3 hours of administration and plasma level at 6 hour was only 4.4±2.0 μg/ml. The renal clearance of sulfamethoxazole (22±2.17 ml/min/10 kg) exceeded the creatinine clearance (9.78±1.57 ml/min/10 kg) which may be due to involvement of active tubular secretion and pH dependent back diffusion. Half of the dose of sulfamethoxazole was excreted as unchanged free drug while acetylated amine comprised of 20 percent within the first 6 hours of drug administration.     

Pharmacokinetics, tissue distribution and excretion of gambogic acid in rats.

The plasma pharmacokinetics, excretion, and tissue distribution of gambogic acid (GA), a novel anti-tumor drug, were investigated after intravenous (i.v.) bolus administration in rats. Plasma profiles were obtained after i.v. administration of GA at the doses of 1, 2 and 4 mg/kg. The elimination half-life (tl/2) values for GA were estimated to be 14.9, 15.7 and 16.1 min, while the mean area under concentration-time curve (AUC(t)) values were 54.2, 96.1 and 182.4 microg min/ml, respectively. GA was mainly excreted into the bile (36.5% over 16 h). The cumulative sum of fecal excretion within 48 h was 1.26% of the i.v. administered dose. No GA was detected in the urine after i.v. administration. GA had a limited tissue distribution, with the highest concentrations being found in the liver. GA reached its maximal concentration in all tissues at 5 min post-dose. In conclusion, the present observations indicated that GA was rapidly eliminated from the blood and transferred to the tissues. Moreover, the majority of GA appeared to be excreted into the bile within 16 h of i.v. administration.     

Pharmacokinetics and excretion of unique beta-adrenergic agonists

beta-Adrenergic agonist analogs (congeners) of isoproterenol in which the N-isopropyl group has been linked to a p-methyl- (119) or p-trifluoromethyl- (143) anilide moiety through a four carbon methylene spacer have been investigated with respect to their plasma pharmacokinetic profiles and biliary and urinary elimination characteristics in rats. In spite of the differences in selectivity of pharmacologic effects and durations of action between these unique beta-adrenergic agonists and isoproterenol, no differences were observed in their pharmacokinetic parameters in plasma after intravenous administration. Plasma clearances were rapid (67-78 ml/min) and the compounds were widely distributed. In contrast to the known elimination characteristics of isoproterenol, biliary excretion was the major pathway for elimination of 119 and 143. Parent drug and 'one' major metabolite peak appeared in HPLC chromatograms of bile collected from rats that received 119 and 143 by intravenous administration. Preliminary evidence suggests that this metabolite peak consists of one or more glucuronide and/or sulfate conjugates. Urinary excretion appears to be of lesser quantitative importance for 119 and 143 than for isoproterenol. The protracted duration of residence of the derivatives in the heart may help to explain the unusual effects and tissue-specific pharmacological properties of these unique beta-adrenergic agonists.     

Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline.

The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose-independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single-injection renal clearance method, were 21.25 micrograms/mL for the Michaelis-Menten constant and 102.38 micrograms/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady-state volume of distribution of DPP. The effect of probenecid concentration on the steady-state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid-insensitive transport systems for DPP in the renal proximal tubule. The Michaelis-Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 micrograms/mL.     

Effects of buthionine sulfoximine and diethyl maleate on glutathione turnover in the channel catfish.

Despite the growing use of fish in toxicological studies, little is known regarding glutathione (GSH) metabolism and turnover in these aquatic species. Therefore, we examined GSH metabolism in the liver and gills of channel catfish (Ictalurus punctatus), a commonly employed aquatic toxicological model. Treatment of channel catfish with L-buthionine-S,R-sulfoximine (BSO, 400 or 1000 mg/kg, i.p.), an inhibitor of GSH biosynthesis, did not deplete hepatic GSH in channel catfish. In addition, hepatic GSH concentrations did not fluctuate in catfish starved for 3 days, indicating relatively slow turnover of hepatic GSH. However, hepatic GSH concentrations were reduced significantly (P less than 0.05) after 7 days of starvation. Administration of the thiol alkylating agent diethyl maleate (DEM, 0.6 mL/kg, i.p.) resulted in depletion of 85% of hepatic GSH at 6 hr post-DEM, with complete GSH recovery observed at 24 hr post-DEM. Co-administration of BSO and DEM (1000 mg/kg, 0.6 mL/kg, respectively) substantially depleted gill GSH and eliminated detectable liver GSH. Following BSO/DEM, GSH recovery in hepatic mitochondria occurred more rapidly than did liver cytosolic GSH. gamma-Glutamylcysteine synthetase (GCS) activities were comparable in the 10,000 g supernatants of catfish liver and gills (204 +/- 21 and 268 +/- 20 nmol/min/mg protein, respectively) whereas gamma-glutamyltranspeptidase (GGT) activity was not detected in the 600 g post-nuclear fraction of either liver or gills. In conclusion, i.p. administration of DEM was an effective means for achieving short-term hepatic GSH depletion in channel catfish, whereas co-administration of BSO and DEM elicited prolonged and extensive hepatic GSH depletion in this species. Like rodents, channel catfish maintained physiologically distinct hepatic mitochondrial and cytosolic GSH pools, and also regulated hepatic GSH levels by in situ hepatic GSH biosynthesis. However, unlike rodents, there was no evidence for a labile hepatic cytosolic GSH pool in channel catfish. These similarities and differences need to be considered when designing toxicological studies involving the GSH pathway in channel catfish and possibly other fish species.     

Chlorpyrifos pharmacokinetics and metabolism following intravascular and dietary administration in channel catfish.

The pharmacokinetics and metabolism of a model organophosphorothioate, chlorpyrifos, was investigated in channel catfish (Ictalurus punctatus). Chlorpyrifos exhibited multicompartmental disposition after oral and intravascular administration, indicating slower distribution to peripheral storage tissues. The oral bioavailability of chlorpyrifos was 41%, substantially higher than in mammals. Muscle contained less than 5% of the oral dose, with an elimination half-life of about 3.3 days. Residues in the whole fish were greater than 95% chlorpyrifos, while excreta (bile and urine) primarily contained metabolites. The dephosphorylated metabolite, trichloropyridinol (TCP), was the major metabolite in the blood, while the glucuronide conjugate of TCP was the major metabolite in urine and bile. The toxic metabolite, chlorpyrifos oxon, was not detected in any samples of blood, tissues, or excreta. The metabolism of chlorpyrifos in catfish appeared similar to other species of fish and mammals. Extensive metabolism resulted in a low potential for chlorpyrifos to accumulate in catfish from dietary exposure.     

Pharmacokinetics and excretion of chlorogenic acid in beagle dogs

In order to characterize the pharmacokinetics and excretion of chlorogenic acid (ChA) in beagle dogs, a gradient high performance liquid chromatographic method has been developed and validated for determining ChA concentration in dog serum, urine and feces. The pharmacokinetic profile of ChA in dog after an intravenous injection was best described by a two-compartment model. Terminal half-lifes were similar at dosages of 5, 20 and 50 mg/kg, ranging from 41-45 min, while AUC and Cmax values of ChA were dose proportional. There are no differences in Vd and CL at three doses of ChA, ranging from 133-252 mL/kg and from 4.4-6.3 mL/min/kg respectively. Excretion studies showed that more than 67% ChA was excreted into urine and less than 3% ChA was eliminated into feces.     

羟乙基芦丁在大鼠体内的药物动力学

观察维脑路通注射液中总羟乙基芦丁在大鼠体内的药物动力学。方法：大鼠静脉注射羟乙基芦丁２０,４０和５０ｍｇ·ｋｇ－１后,用反相高效液相色谱多组分峰共积分测定法,测定在不同时间各组织和体液中总羟乙基芦丁的含量以及蛋白结合率。结果：羟乙基芦丁在血浆中的药物动力学符合一室开放模型,有关参数除Ｃｌ外,血浆蛋白结合率、Ｃｏ、Ｔ１／２（３．０１～５．３３ｈ）、Ｖｃ（２．４０～４．１６Ｌ）、ＡＵＣ（３６．２６～９２．３８ｍｇ·ｈ·Ｌ－１）均具有剂量依赖性,药物血浆蛋白结合率的６２％,药物在体内各组织分布广泛且含量相差不大,但脂肪组织中最低,给药８ｈ后各组织中含量明显下降,在粪、尿和胆汁中原形药物总排出量占给药量（４０ｍｇ·ｋｇ－１）的１１．７％。实验中建立的高效液相色谱法适于体内羟乙基芦丁的测定,检测下限为１μｇ·Ｌ－１,线性范围０．１～１５ｍｇ·Ｌ－１。结论：羟乙基芦丁在大鼠体内各组织分布广泛,主要经代谢途径被清除。