Pharmacokinetics of dolasetron following single- and multiple-dose intravenous administration to normal male subjects

Dolasetron, Anzemet^TM, a 5-hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto-reduced metabolite of dolasetron has been identified in human plasma and is probably responsible for the majority of the antiemetic activity. This study evaluated the pharmacokinetics of dolasetron and the reduced metabolite following single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active/two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg^?1 on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg^?1 d^?1 on days 2–9. Dolasetron could be detected for less than 1 h, while the reduced metabolite appeared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolite maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half-life of reduced metabolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduced metabolite was 2.20–4.43 mL min^?1 kg^?1 and was dose independent. All of the evidence supports dose independent pharmacokinetics for the reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single-dose pharmacokinetics of this metabolite.     

Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats

The pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg^?1 (high dose) or 0.49 mg kg^?1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high-pressure liquid chromatographic (HPLC) method. AGN 190168 was rapidly metabolized in rats. The only detectable drug-related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non-linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (V_max) and the concentration at half of the V_max (k_m), as estimated by a Michaelis—Menten one-compartment model, were 7.58 ± 2.42 μg min^?1 (mean ± SD) and 6.10 ± 1.58 μg mL^?1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL^?1 after administration of the high dose and 0.594 ± 0.095 μg h mL^?1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min^?1 kg^?1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min^?1 kg^?1. The terminal half-life (t_1/2) was 1.25 ± 0.74 h for the high-dose group and 0.95 ± 0.16 h for the low-dose group. Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non-linear pharmacokinetics of AGN 190299 after the 4.4 mg kg^?1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.     

Pharmacokinetics of bicyclol in rats with acute hepatic failure

The aim of present study is to evaluate the pharmacokinetics of bicyclol in carbon tetrachloride (CCl₄)-intoxicated rats. The plasma concentration of bicyclol was detected in rats after a single oral or intravenous administration by high-performance liquid chromatography (HPLC) analysis. Rat intestinal and hepatic perfusion models were employed to clarify the respective effect of gut and liver on the pharmacokinetics of bicyclol in acute hepatic failure (AHF) rats. Rat in vitro microsomal incubation was also conducted. The bioavailability of bicyclol was increased 3.1-fold after CCl₄ intoxication in rats. The area under the curve (AUC)_(0–∞), C_max, and clearance (CL) of bicyclol after intravenous administration were 13.4 mg h l^?1, 18.8 mg l^?1, and 1.8 l h^?1 kg^?1 in control rats, and 130 mg h l^?1, 33.1 mg l^?1, and 0.15 l h^?1 kg^?1 in AHF rats, respectively. In the present study we investigated the pharmacokinetics of bicyclol in CCl₄-intoxicated rats and differentiated the respective role of intestine and liver by using in situ intestinal and hepatic perfusion in rats, and in vitro rat microsomes incubation. The studies are expected to provide a better understanding related to the alteration of pharmacokinetics of bicyclol in pathological situation.     

Pharmacokinetic Study of Zonisamide in Patients Undergoing Brain Surgery

To test whether the concentration of the anticonvulsant zonisamide in erythrocytes reflects the brain concentration and the clinical response of the drug, its pharmacokinetics were studied in nine patients undergoing surgery for brain tumour. Erythrocyte, total, and free serum concentrations in samples drawn on the day of brain surgery were compared with levels on a day after the operation. In three patients zonisamide and its major metabolite, 2-sulphamoylacetylphenol, were also analysed in urine. The area under the curve of the free and the erythrocyte concentration did not differ between the two study phases whereas the area under the curve of the total serum concentration was significantly lower on the day of the operation, and this was associated with significant increases in total clearance (15.4 compared with 12.7 mL kg^?1 h^?1, P < 0.05, n = 9) and renal clearance (5.4 compared with 3.3 mL kg^?1 h^?1, P < 0.05,n=3), and non-significant change in non-renal clearance (7.7 on the day of operation compared with 8.4 mL kg^?1 h^?1 on the post-operation day, n = 3). Zonisamide distribution was also altered by the operative procedure, as evidenced by a higher volume of distribution (1.48 compared with 0.87 L kg^?1, P < 0.05, n = 9). The binding of zonisamide was characterized on both days. Zonisamide binding to erythrocytes seemed to occur by two processes: a saturable process and a non-saturable linear process. The maximum binding capacity to erythrocytes (31.6 vs 29.7 μg mL^?1) did not differ on the two days; however, increases in the dissociation binding constant (+28%) and the proportionality constant (+24%) were observed on the day of the operation, suggesting that the zonisamide concentration in erythrocytes was greater on the day of the operation. Brain surgery appears to be one of the possible factors altering the rate of elimination of zonisamide and the uptake of the drug by erythrocytes.     

Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism

1. The objective of this study was to investigate the effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism.

2. After oral administration of diammonium glycyrrhizinate (50?mg kg^?1), the peak plasma concentration (C_max), area under the plasma concentration–time curve from zero to time τ (AUC_0–τ), and absolute bioavailability of aconitine (0.2?mg kg^?1) significantly increased 1.64-, 1.63- and 1.85-fold, respectively, but there was no significant change in half life (t_1/2) or clearance (CL). In the other two routes of administration via the tail vein and hepatic portal vein, diammonium glycyrrhizinate (15?mg kg^?1) did not affect any of the pharmacokinetic parameters of aconitine (0.02?mg kg^?1). Thus, diammonium glycyrrhizinate can enhance the absorption of aconitine, leading to higher oral bioavailability and plasma levels, but it does not influence its elimination.

3. Moreover, an in vitro everted gut sac model and Ussing chamber model were used to investigate the potential mechanism. Results from bidirectional transport and inhibition studies demonstrated that P-glycoprotein was the main efflux transporter involved in the absorption of aconitine in rats. The absorption enhancement effect of diammonium glycyrrhizinate should be mainly attributed to inhibiting the activity of P-glycoprotein rather than to the influence on the paracellular or transcellular transport.     

Effects of Sho-saiko-to on the Pharmacokinetics and Pharmacodynamics of Tolbutamide in Rats

Although Sho-saiko-to (Xiao Chai Hu Tang), a major Chinese traditional medicine, is frequently prescribed with other synthetic or biotechnological drugs for the treatment of various chronic diseases, there is a dearth of information about interactions between sho-saiko-to and co-administered drugs. This paper reports the effects of Sho-saiko-to on the pharmacokinetics and glucose responses of a sulphonylurea hypoglycaemic agent, tolbutamide, after their oral administration in rats. After oral administration of tolbutamide (50 mg kg^?1) with or without Sho-saiko-to extract powder (300 mg kg^?1) to male Sprague-Dawley rats cannulated in the jugular vein, plasma tolbutamide and glucose levels were periodically measured. Co-administration of Sho-saiko-to tended to elevate the plasma tolbutamide concentration in the absorption phase. A two-compartment lag-time model was found to describe the plasma tolbutamide concentration-time data. The maximum concentration of tolbutamide was significantly increased and time to reach the maximum concentration was reduced to about 70% by co-administration with Sho-saiko-to. There was no significant change in area under the curve or in the elimination half-life of tolbutamide. The extent of the lowering effect of tolbutamide on plasma glucose levels was increased up to 0.75 h and decreased after 5 h after co-administration of Sho-saiko-to. In conclusion, these studies suggest that sho-saiko-to slightly hastens the gastrointestinal absorption of tolbutamide. Furthermore, it is considered that elevation of the gastrointestinal absorption rate by Sho-saiko-to might potentiate the hypoglycaemic effect of this sulphonylurea in the early period after oral administration.     

Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

Pharmacokinetic and Pharmacodynamic Studies of the Histamine H1-Receptor Antagonist Ebastine in Dogs

Abstract— The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0·01 mL of a 0·2 mg mL^?1 histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4·38 ± 1·01 h after 10 mg ebastine and 4·09 ± 0·74 h after 20 mg ebastine; the distribution volume was 3·99 ± 0·88 and 3·65 ± 0·75 L kg^?1 after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0·67 ± 0·24 L h^?1 kg^?1 and after 20 mg ebastine was 0·63 ± 0·17 L h^?1 kg^?1. The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0·001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3–4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0·17 and 0·22 h^?1 after 10 and 20 mg ebastine with a half-life of 4·13 and 3·56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18·9 ± 4.8 ng mL^?1 after 10 mg and 18·2 ± 5.7 ng mL^?1 after 20 mg ebastine.     

A dose-dependent pharmacokinetic study on caffeic acid in rabbits after intravenous administration

The dose-dependent pharmacokinetics of caffeic acid (CA) were studied in rabbits. Three different doses (5, 10, and 25 mg kg⁻¹) were administered intravenously to six rabbits each. The concentration–time profiles for CA could be fitted by a two-compartment model for each dose. The results showed that total-body clearance and elimination rate constant from the central compartment (k₁₀) after a 5 mg kg⁻¹ dose were greater than those after the other two doses. Furthermore, the terminal elimination half-life (β half-life) and mean residence time (MRT) after a 5 mg kg⁻¹ dose were less than after the other doses. The AUC value increased linearly with dose within the range of 10–25 mg kg⁻¹. Most of the unchanged caffeic acid was excreted in the urine within 2 h. The percentage of unchanged caffeic acid excreted in the urine was 63·4, 60·0, and 55·4% after doses of 5, 10, and 25 mg kg⁻¹, respectively, which was not significantly different. However, significant differences in the renal clearances and renal excretion rate constants were observed with a 5 mg kg⁻¹ dose compared to the other doses. On the other hand, nonrenal clearances and nonrenal excretion rate constants showed no dose-related differences. The differences observed in total-body clearance, k₁₀, β half-life, and MRT between a 5 mg kg⁻¹ dose and the other doses can be explained on the basis of the differences in renal clearance and renal excretion rate constants. ©1997 John Wiley & Sons, Ltd.     

The pharmacokinetic assessment of sodium cromoglycate

The plasma concentration of sodium cromoglycate (SCG) was measured in four healthy subjects by radioimmunoassay after a 4 mg intravenous dose and after inhaling from 20 mg capsules, and from 10 and 30 mg ml^?1 nebulizer solutions. The mean absorption constant (K₁) after inhalation was 0·43 h^?1. The mean elimination constant from the plasma (K_elim) after intravenous administration was 11·5 h^?1, and that after inhalation was similar. The apparent volume of distribution of SCG (V_dβ) was 0·2 litre kg^?1 and the mean plasma clearance was 0·35 litre h^?1kg^?1. The amount of SCG absorbed after inhalation varied according to the method of inhalation and dose. After the inhalation of powder from 20 mg capsules, 1·30–3·96 mg reached the plasma, after inhalation of SCG produced by nebulizing a 10 mg ml^?1 solution for 5 min at 10 psi using a Minineb nebulizer 0·19—0·31 mg reached the plasma and when the solution was increased to 30 mg ml^?1 the figure was 0·33—0·45 mg.     

The influence of vitamin C on antipyrine pharmacokinetics in elderly men

The influence of vitamin C on the pharmacokinetics of antipyrine was investigated in eleven elderly men aged 65–74. Antipyrine (15 mg kg^?1) was administered intravenously on three separate occasions over a 7-week period: (a) before dietary vitamin C restriction, (b) after approximately 5 weeks of dietary vitamin C restriction, and (c) after 2 weeks of vitamin C supplementation (500 mg orally twice daily). The mean plasma and leucocyte vitamin C levels (±S.D.) before vitamin C restriction were 1·26 ± 0·31 mg dl^?1 and 26·6 ± 6·7 μg 10^?8 leucocytes, respectively. These values decreased and then increased significantly following vitamin C restriction and supplementation, respectively. The mean plasma half-life of antipyrine was 10·2h and the mean plasma clearance was 2·561h^?1 1·73 m^?2 before vitamin C restriction. No significant changes in the clearance, volume of distribution, or half-life of antipyrine occurred during the study, indicating that short-term alterations in vitamin C intake do not affect the pharmacokinetics of antipyrine in elderly males.     

A Pharmacokinetic-pharmacodynamic Linking Model for the α2-Adrenergic Antagonism of Idazoxan on Clonidine-induced Mydriasis in the Rat

The relationship between concentration and inhibitory effect of the α₂-adrenoceptor antagonist idazoxan on clonidine-induced mydriasis has been studied in the rat using pharmacokinetic-pharmacodynamic simultaneous modelling. Fifteen minutes after the anaesthesia of rats with sodium pentobarbitone (55 mg kg-1, i.p.), and 5 min after the administration of clonidine (0·3 mg kg^?1, i.v.) to rats pretreated with idazoxan (3 mg kg^?1, i.v., and 3 and 10 mg kg^?1, orally) at different time intervals, pupil diameters were assessed. The pharmacokinetics of idazoxan were adequately described by a monoexponential equation. Using a pharmacokinetic-pharmacodynamic linking model, the concentration-effect relationships of idazoxan were derived, and were quantified by the inhibitory simple E_max model. At the effect compartment, the estimated apparent IC50 was 153·6 ng mL^?1. Values of clearance, volume of distribution and elimination half-life were 71·2 mL kg^?1 min^?1, 3134 mL kg^?1 and 30-5 min, respectively. These results could contribute to better characterization of the pharmacodynamic and toxicological profiles of idazoxan in experimental models in which a different pharmacokinetic behaviour of the drug is presumed.     

Liver and Gastrointestinal First-pass Effects of Azosemide in Rats

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg^?) and intraportal (5 and 10 mg kg^?) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg^?) of the drug was significantly lower than that after intravenous administration (5 mg kg^?) of the drug (1000 vs 1270 μg min mL^?) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC_{0–8 h}) after oral administration (5 mg kg^?) of the drug was considerably smaller than that after intraportal administration (5 mg kg^?) of the drug (271 vs 1580 μg min mL^?) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC_{0–8 h} after oral administration (5 mg kg^?) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg^?) of the drug (271 vs 320 μg min mL^?), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.     

Accelerated metabolism of probenecid during long-term treatment of rats with anticonvulsant drugs: effect on central serotonin turnover studies

Studies were carried out in rats to determine the effects of long-term administration (once daily for 9 days) of phenytoin (50 mg kg^?1), sodium phenobarbital (25 mg kg^?1), primidone (50 mg kg^?1), and l-5-hydroxytryptophan (l-5-HTP; 50 mg kg^?1) on probenecid metabolism and on serotonin turnover rates as estimated by probenecid-induced accumulation of 5-hydroxyindoleacetic acid (5-HIAA) in brain. Without probenecid, mean brain 5-HIAA levels were similar in control and drugtreated rats, suggesting that the turnover rate of brain serotonin was not affected by the chronic anticonvulsant drug pretreatment. But, in the rats treated with phenobarbital, the rate of accumulation of 5-HIAA in brain during the first 90 min after probenecid (200 mg kg^?1) was significantly lower than the rate of accumulation in the control rats. Also, at 6 hr after probenecid, brain 5-HIAA levels were similar to pre-probenecid values in the rats pretreated with phenobarbital or primidone, while 5-HIAA levels were still increased in the rats treated with phenytoin, l-5-HTP, or vehicle. Examination of serum revealed that the concentration of probenecid in serum decreased more rapidly in rats pretreated with either primidone or phenobarbital than in rats given vehicle, l-5-HTP, or phenytoin. It is likely, therefore, that the decreased 5-HIAA accumulation in the brains from these animals were due to decreased inhibition of 5-HIAA efflux and not to a decreased rate of serotonin turnover in brain. Since a sustained inhibition of acid transport by probenecid is required, drug interactions with probenecid may be important in clinical studies using probenecid-induced accumulations of 5-HIAA in cerebrospinal fluid to estimate central serotonin turnover rates.     

Pharmacokinetics of Intragastrically Administered Digoxin in Rabbits with Experimental Bile Duct Obstruction

A change in the functioning of the liver as a result of experimental cholestasis could result in a change in the biotransformation of drugs. The aim of this study was to evaluate the effect of extrahepatic cholestasis on the pharmacokinetics of digoxin. The investigation was performed on male rabbits randomly divided into two groups: sham-operated and animals with bile-duct ligation. Digoxin (0.02 mg kg^?1) was administered intragastrically as a single dose. Biomedical and anatomo-pathological tests and pharmacokinetic assays were performed before the operation and on the 6th day after surgery. A significant increase in area under the serum concentration-time curve and in mean residence time, a decrease in total body clearance, a reduction in the volume of distribution and increases in maximum concentration and the time to reach maximum concentration were observed in animals with the bile-duct ligation. These results suggest reduced elimination of digoxin in animals with obstructive cholestasis.     

Effects of acute and subacute treatment with ergot drugs on the GABA system in specific brain regions

The effect of dihydroergotoxine and dihydroergotamine on Γ-aminobutyric acid (GABA) levels, the aminooxyacetic acid (AOAA)-induced accumulation of GABA, and the in vitro activity of L-glutamate decarboxylase (GAD) have been examined in various regions of rat brain. Dihydroergotoxine (1 mg kg^?1) decreased the concentration of GABA and enhanced the AOAA-induced accumulation of GABA in the caudate nucleus and cingulate cortex. Dihydroergotoxine 10·0 mg kg^?1 decreased the AOAA-induced accumulation of GABA in the substantia nigra. The repeated treatment with dihydroergotoxine, 0·05 mg kg^?1 for eight days, also decreased the concentration of GABA in the cingulate cortex and diminished the AOAA-induced accumulation of GABA in the substantia nigra. The administration of 0·1 mg kg^?1, but not higher doses; of dihydroergotamine, enhanced the AOAA-induced accumulation of GABA in the cingulate cortex. Dihydroergotamine (10·0 mg kg^?1) decreased the concentration of GABA in the cingulate cortex and increased the AOAA-induced accumulation of GABA in the caudate nucleus. The activity of GAD in the cingulate cortex, but not in the caudate nucleus, was enhanced after a high dose of dihydroergotamine. Observed increases in the AOAA-induced accumulation of GABA indicate that dihydroergotoxine and dihydroergotamine in at least some brain areas cause an apparent increase in GABA syn-synthesis in vivo, which is presumably a compensatory phenomenon due to a diminished GABAergic transmission under the influence of these drugs.     

Pharmacokinetics and Tissue Distribution of (±)-3′-Azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine,a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (AZT) in Mice

The in-vivo biodistribution and pharmacokinetics in mice of 3′-azido-2′,3′-dideoxythymidine ( 1 , AZT), 2-bromomyristic acid ( 2 ) and their common prodrug, (±)-3′-azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine ( 3 ) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver. The pharmacokinetics of AZT (βt1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 ± 2.9 μmol g^?1 min; CL (blood clearance) = 10.5 ± 1.1 mL min^?1 kg^?1) and its ester prodrug ( 3 , βt1/2 = 428.5 min; AUC = 17.3 ± 4.7 μmol g^?1 min; CL = 17.6 ± 4.8 mL min^?1 kg^?1) were compared after intravenous injection of equimolar doses (0.3 mmol kg^?1) via the tail vein of Balb/c mice (25.30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 μmol g^?1) and AUC (12.3 μmol min g^?1) were lower than observed after AZT administration (peak concentration 0.36 μmol g^?1; AUC 29.1 μmol min g^?1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 μmol g^?1; respective AUCs 42.5 and 12.7 μmol min g^?1). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g^?1) and AUCs (2.8 compared with 1.4 μmol min g^?1). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.     

Drug distribution and a pulmonary adverse effect of intraperitoneally administered doxorubicin niosomes in the mouse

Niosomes (non-ionic surfactant vesicles) prepared from C₁₆G₂ (a hexadecyl-diglycerol ether), and loaded with doxorubicin, were administered intraperitoneally to male AKR mice at dose levels of 0, 2.5, 5.0, and 10.0 mg kg^?1. Free drug was given at 10.0 mg kg^?1 by the intraperitoneal route. At a dose level of 10.0 mg kg^?1, peak doxorubicin levels in the central compartment were attained faster with the free drug than with the niosome formulation. However, the peak plasma levels were similar for the free drug and the niosome preparation at the 10 mg kg^?1 dose level. With doxorubicin administered as the niosome preparation by the intraperitoneal route at 2.5, 5.0, and 10.0 mg kg^?1, mean peak plasma concentrations of the drug showed a tendency to be dose-related although the differences were not significant. Over the 24 h period of the experiment, with doxorubicin at 10 mg kg^?1, the niosome formulation delivered significantly more drug to the plasma compartment than the free drug (p <0.05). When doxorubicin was given in niosomes at 2.5, 5.0 and 10.0 mg kg^?1 by the intraperitoneal route, the resulting levels of doxorubicin in cardiac tissue were not dose related and the differences not significant and, although the mean peak cardiac-tissue concentration was higher in animals receiving the free drug at 10.0 mg kg^?1 intraperitoneally than in mice given intaperitoneal doxorubicin niosomes at this dose level, the differences were again not significant. There were clinical signs of toxicity in mice given doxorubicin-containing niosomes intraperitoneally at 5.0 and 10.0 mg kg^?1, and at post-mortem an accumulation of fluid in the pleural cavity was evident. These changes were not seen in mice dosed intraperitoneally with free drug at 10 mg kg^?1, or in animals given doxorubicin niosomes intraperitoneally at 2.5 mg kg^?1. In mice dosed intraperitoneally with doxorubicin niosomes at 12.0 mg kg^?1 and at a dose volume of 0.2–0.4 mL, histological examination of the lungs demonstrated a congestion of the alveolar capillaries, and an increased number of acute inflammatory cells in the alveolar walls. There was no histological evidence of lung toxicity in mice dosed with doxorubicin niosomes at 12.0 mg kg^?1 when the formulation was administered with the higher dose volume of 1.8–2.0 mL. Importantly there was no histological evidence of lung toxicity in mice dosed with empty niosomes intraperitoneally or with doxorubicin niosomes given itravenously at 12.0 mg kg^?1.     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.