Disposition of single oral doses of butylated hydroxytoluene in man and rat

The kinetics and metabolism of butylated hydroxytoluene (BHT) in man and rats have been compared. Single oral doses of 200, 63 or 20 mg BHT/kg body weight were administered to rats and a single oral dose of 0.5 mg/kg body weight was ingested by human volunteers (non-smoking males). In rats, kinetic parameters (area under the plasma concentration-time curve, plasma BHT peak levels) showed a dose-dependent increase. Plasma BHT levels after oral administration were about four times higher than those that have been reported for another synthetic food antioxidant, butylated hydroxyanisole (BHA; Verhagen et al., Fd Chem. Toxic. 27, 151–158). This may be a reflection of a smaller volume of distribution for BHT, since there were no differences in plasma elimination half-life or plasma clearance between BHT and BHA. In man, the mean plasma concentration-time profile after oral BHT intake was well below the BHT profiles observed for rats and closely followed plasma BHA kinetics in man. In rats, the simultaneous administration of BHT (200 mg/kg body weight) and BHA (200 mg/kg) significantly decreased the absorption of BHT from the gastro-intestinal tract in the first few hours after treatment; the plasma kinetics of BHA were not influenced by the simultaneous administration of BHT. In human female volunteers no alterations in plasma BHT or BHA profiles were seen after the simultaneous ingestion of BHT (0.25 mg/kg body weight) and BHA (0.25 mg/kg). Rats excrete about 10% of an oral dose of 200 mg BHT/kg as unchanged BHT in the faeces, whereas in man no BHT could be detected in the faeces. Urinary excretion of (un)conjugated 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH) accounts for only a small percentage of the administered dose in both rats and humans. It is concluded that the plasma BHT concentrations reached after the administration of a single medium to high dose of BHT to rats or a single low dose to man are very different.     

Disposition of quercetin in man after single oral and intravenous doses

Summary The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8±1.2 min for the phase and 2.4±0.2 h for the phase (predominant half life), respectively. Protein binding was >98%. The apparent volume of distribution was small at 0.34±0.03 l/kg. Of the intravenous dose 7.4±1.2% was excreted in urine as a conjugated metabolite, and 0.65±0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53±5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.Supported by grant Gu 86/3 from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Germany (FRG).     

Disposition of chloroquine in man after single intravenous and oral doses.

1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half-life from 146 to 333 h. Total plasma clearance +/- s.d. was 712 +/- 166 ml/min and renal clearance 412 +/- 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole.     

A new metabolite of butylated hydroxyanisole in man

Butylated hydroxyanisole (I) is one of the most commonly used food antioxidants. Its use has been suggested to inhibit a variety of carcinogenic responses. The present study on the disposition kinetics of (I) in man indicates that contrary to previous reports, (I) undergoes significant O-demethylation in the body yielding a tert-butyl hydroquinone. It is suggested that this metabolic conversion may be responsible for some of the in vivo activities of (I) against chemical carcinogens.     

Cytotoxicity of butylated hydroxyanisole and butylated hydroxytoluene in isolated rat hepatocytes

The effects of the antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on isolated rat hepatocytes were investigated. Both antioxidants were observed to be cytotoxic in a concentration-dependent manner at concentrations ranging from 100 to 750 microM. At equimolar concentrations BHT was more cytotoxic than BHA. Their toxicity appeared to be independent of their metabolism to reactive intermediates since inhibitors of cytochrome P-450 (metyrapone, SKF 525-A and piperonyl butoxide) had no effect on the cytotoxicity and N-acetylcysteine was also without protective effect. In addition, deuterated BHT was equitoxic with BHT. Only low temperature incubation (4 degrees), which has previously been shown to inhibit the insertion of these compounds into biomembranes, was effective in inhibiting the cytotoxic effects. Using isolated rat liver mitochondria we observed that both BHA and BHT inhibited respiratory control primarily by stimulating state 4 respiration and thus acting as membrane uncouplers. BHA and BHT also effectively dissipated membrane potential across the mitochondrial membrane and caused the release of calcium and mitochondrial swelling. These mitochondrial effects were reflected by a rapid decrease in ATP levels in intact hepatocytes which preceded cell death. These results suggest that the observed cytotoxicity of BHA and BHT to hepatocytes is related to their effects on biomembranes and mitochondrial bioenergetics.     

Lung hemorrhagic toxicity of butylated hydroxyanisole in the rat

Male Sprague-Dawley rats were injected intraperitoneally (i.p.) with butylated hydroxyanisole (BHA) at doses of 0, 1, 4, 16, 64, 256, 384, 576, 864, 1296 and 1944 mg/kg/day for 7 days. Deaths occurred in a dose- and time-dependent manner when BHA was given in amounts greater than 576 mg/kg. The LD50 was 881 (484-1440) mg/kg. Intracranial hemorrhage was found in the dead rats, and lung hemorrhage was observed in the survivors given BHA at doses greater than 384 mg/kg/day. Histopathologically, intra-alveolar hemorrhages, thickening of alveoli and deposition of lipids in the lungs were observed. The prothrombin index was decreased only in rats given BHA at a level of 384 mg/kg/day. These observations suggest that BHA and/or its metabolite cause pulmonary hemorrhagic damage in rats. The mechanism of hemorrhage may be different from that of bleeding induced by butylated hydroxytoluene.     

Disposition rate of proscillaridin A in man after multiple oral doses

After multiple oral doses, the disposition rate constant (beta) of proscillaridin was studied in 4 young healthy volunteers and 33 elderly patients with congestive heart failure. Glycoside activity in plasma was assayed by the 86Rb-technique. In the volunteers the beta averaged 0.0299 corresponding to a half-life (t 1/2) of 23 h. beta could be determined in 24 patients and was 0.0139 +/- 0.0077 (mean +/- SD). The SD of beta due to biological factors was estimated to be 0.0072. The total variation of beta was 10fold. The mean beta corresponded to a t 1/2 of 49 h with a range from 19 to 209 h. It is concluded that the great variation of beta means difficulty in obtaining adequate plasma levels of proscillaridin and that a rapid elimination of the glycoside cannot be presumed.     

Dextropropoxyphene kinetics after single and repeated oral doses in man

Summary The kinetics of dextropropoxyphene (DP) and its main metabolite norpropoxyphene (NP) were studied in 6 healthy male subjects after a single oral dose of 195 mg DP HCl, and during and after 12 daily single oral doses of 195 mg DP HCl. The kinetics varied up to five-fold between individuals after the single dose, the apparent mean elimination half-life (t_1/2) was 16 h for DP and 29 h for NP. The mean apparent overall plasma clearance (CL) for DP was 2.61/min. There was no systematic difference in DP clearance between the single and multiple doses, but the accuracy of individual predictions from single to multiple doses was poor, probably because of imprecise determinations of the AUC and t_1/2 in the single dose experiments. The individual correlation between single and multiple dose kinetics was good for NP, although the predicted plasma levels during steady state were significantly higher than the observed levels (mean AUC_ss/AUC_sd: 0.81). There was no sign of saturation kinetics on repeated administration. In fact, autoinduction, resulting in significantly lower plasma concentrations after treatment for 1 week was found for NP and was indicated for DP. On discontinuing DP after 12 days of treatment, the apparent mean t_1/2 of DP was 23 h and of NP 25 h.     

Pharmacokinetics of fluoride in man after single and multiple oral doses

Summary The doses of fluoride (F) recommended in the literature for caries prevention and for the treatment of osteoporosis vary. This partly reflects inadequate knowledge of F pharmacokinetics. In the present study various single and multiple oral doses of F were given to eight volunteers, who had a strictly controlled F intake in the diet. The resulting plasma and parotid saliva concentrations as well as urinary output of F were measured. The plasma data fitted a two-compartment open model with a -slope half-life ranging between 2 and 9 h. Plasma clearance was 0.15±0.02 (SD) liter/kg/h. Data from the highest dose (10 mg) were fitted to both two- and three-compartment models, and there was no significant difference between them. Multiple doses of F 3.0 or 4.5 mg yielded steady state concentrations ranging from 54 to 145 ng/ml. About 50 per cent of the given dose was recovered in the urine, which is indicative of considerable accumulation in the body. The saliva F/plasma F concentration ratio was 0.64 with a coefficient of variation of 5%.     

Plasma kinetics of methaqualone in man after single oral doses

Summary Plasma concentrations of methaqualone were followed for several days after single oral doses in 5 healthy subjects. The analysis of methaqualone was performed by gas chromatography-mass spectrometry (mass fragmentography). The plasma levels of methaqualone were interpreted according to a two compartment model. The elimination rate of methaqualone was found to be much slower than has been reported previously, half lives in the -phase ranging from 19.6 to 41.5 h.     

Pharmacokinetics of butobarbital after single and multiple oral doses in man

Summary A method is described for the assay of therapeutic levels of butobarbital (5-ethyl-5-n-butylbarbituric acid) in human plasma, which involves a single extraction step followed by gas chromatography with alkali flame ionization detection. The pharmacokinetics of butobarbital were studied in five healthy volunteers after oral administration of 200 mg. Plasma concentrations were determined at regular intervals up to 96 h and the data were fitted by non-linear, least squares regression analysis according to one-compartment kinetics. The average lag time was 0.11 h and the absorption half-life 0.21 h. The elimination half-life varied from 33.6 to 41.5 h with an average of 37.5 h. Four of the volunteers participated in a study of multiple dosing (every 24 h) during which substantial accumulation of butobarbital was observed. The elimination half-life after termination of drug administration had decreased to about 20–25% of its initial value, probably because of enzyme induction. It was concluded that butobarbital could not be regarded as a suitable drug for treatment of insomnia, since CNS depressant effects were likely to persist into the following day. Repeated administration of butobarbital should be avoided and its incidental use restricted to patients who require day-time sedation.     

Effect of butylated hydroxyanisole on electron transport in rat liver mitochondria

The effects of butylated hydroxyanisole (BHA), a commonly used food antioxidant, on oxygen consumption, ATPase activity, and the redox state of some electron carriers of rat liver mitochondria have been studied. It was observed that BHA slightly stimulated state 4 respiration but strongly inhibited ADP- and uncoupler-stimulated respiration on NAD(+)- and FAD-linked substrates. ATPase activity and vectorial H+ ejection were affected only slightly by BHA, suggesting that BHA predominantly inhibits mitochondrial electron flow. Experiments to determine its site of action showed that BHA did not noticeably affect electron flow through cytochrome oxidase; in contrast, NADH:duroquinone reductase activity and electron flow through ubiquinone-cytochrome b-cytochrome c complex were inhibited strongly because the oxidation of duroquinol was affected markedly. The BHA block of electron transport was bypassed by both N,N,N',N'-tetramethyl-p-phenylenediamine and 2,6-dichlorophenolindophenol. Also, the presence of BHA changed the redox state of cytochrome b and c1 to a more oxidized level. These observations suggest that electron transport is inhibited by BHA at the NADH-ubiquinone and at the ubiquinone-cytochrome b levels. From Hill plots, it is clear that more than one binding site is involved in complete inhibition; in addition, available evidence suggests that there may be two sites at the substrate side of ubiquinone and another two sites at the oxygen side of ubiquinone. Consequently, mitochondrial ATP synthesis would be interrupted. This event could be related to the toxicity of BHA.     

Manipulation of mouse organ glutathione contents I: Enhancement by oral administration of butylated hydroxyanisole and butylated hydroxytoluene

Administration of either butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) (1000 mg/kg/day for 5 days) to male mice increased the content of reduced glutathione by 50-100% in liver, lung, duodenum and intestine. In colon, glandular stomach, spleen and kidney no effect on glutathione level was observed. BHA and BHT led also to 100-1000% induction of glutathione transferases in liver, lung (only BHA), kidney and digestive tract (except the colon); the relative increase in transferase activity was greater with 1-chloro-2,4-dinitrobenzene (DCNB) as a substrate than with CDNB in all organs investigated. The effects of BHA, administered in olive oil by gavage, on different parts of the gastrointestinal tract revealed maximum increase of the glutathione content and transferase activities in the duodenum, smaller increase of these parameters in the upper intestine and no significant effects in the lower intestine and the colon. Starving mice for 1 day decreased the glutathione content of the liver by 50% to 21.3 +/- 4.5 nmol/mg protein in controls and to 39.4 +/- 3.3 in BHA-treated animals. Intravenous injection of 0.5 mmol GSH/kg restored the fed state (C: 37.4 +/- 2.8 nmol GSH/mg protein; BHA: 84.9 +/- 7.7) within 2 h. This indicates a much faster de novo synthesis of liver glutathione in BHA-pretreated animals. The mechanistic aspects of phenolic antioxidant effects on GSH metabolism are discussed.     

Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses

OBJECTIVES: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating species metabolites after oral administration of N. Bioavailability is substantially increased by food. The objectives of this phase IA study were to assess the tolerability and to determine the pharmacokinetic linearity of T and TG after single oral administration of increasing doses of N with and without food in healthy volunteer subjects. METHODS: Thirty-two healthy male volunteers were randomly assigned to 1 of 4 treatment groups. In each successive group, 2 subjects received a placebo and 6 received a single oral dose of 1 g, 2 g, 3 g, or 4 g of N, first under fasted conditions and a week later with a standardized breakfast. Blood samples were collected during 24 h for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded. RESULTS: Tolerability was good up to the maximum dose of 4 g. Mild, mostly gastrointestinal side effects were observed and their frequency increased significantly with the dose level. No significant changes were noted in the ECGs, vital signs and laboratory tests. Plasma concentrations increased linearly with the dose from 1 - 4 g, although a trend to increased bioavailability was observed at 4 g. Food approximately doubled the concentrations of T and TG irrespective of dose. Peak times and apparent half-lives increased in proportion to the dose. The apparent body clearance for total T (T+TG) at the highest dose was only half that at the low dose. TG was eliminated more slowly than T. CONCLUSION: Nitazoxanide can be safely administered up to 4 g single oral doses, with or without food. The slow elimination of TG and the overproportional concentrations at the highest dose can be accounted for by solubility- or transport-limited elimination mechanisms becoming apparent at the upper dose level.     

Central effects of single oral doses of propranolol in man.

The central effects of propranolol, a lipophilic beta-adrenoceptor antagonist, were investigated in six healthy male volunteers using two flash fusion threshold (2FFT), simple reaction time (SRT), digital copying test (DCT), symbol digit modalities test (SDMT), Gibson spiral maze test (GSMT) and mood rating scales for tension, alertness, depression, detachment and anxiety. Compared to placebo, 2FFT was prolonged by propranolol 40, 80 and 160 mg at one or more times tested but not by propranolol 320 mg: the largest effect was seen at 3 h after 40 mg, and the effects of 40, 80 and 160 mg were significantly greater than 320 mg at 2 h. SRTs were significantly prolonged by all doses of propranolol at 2 and 3 h and by 40 and 80 mg doses at 5 h. DCT was lowered by 40 and 80 mg at 2 and 3 h by 80 mg at 5 h, and by 320 mg at 2 h, but the 160 mg dose had no effect. Propranolol impaired the expected retest gain of the SDMT with all doses except 320 mg and at 2 h after 40, 80 and 160 mg, performance was actually worsened. Mood rating scales showed increased detachment with 40 mg and decreased alertness with 80 and 320 mg. The results show that propranolol has central effects in man: the effects appeared to be greater with lower doses, 40 and 80 mg, than with higher doses, 160 and 320 mg.     

超高效液相色谱法测定辛伐他汀胶囊中叔丁基-4-羟基茴香醚与2,6-二叔丁基对甲酚的含量

目的建立超高效液相色谱法同时测定辛伐他汀胶囊中的抗氧剂叔丁基-4-羟基茴香醚(BHA)与2,6-二叔丁基对甲酚(BHT)。方法色谱柱为ACQUITY UPLCTM BEH C18(50mm×2.1mm,1.7μm)。以乙腈(A)-0.005mol.L-1醋酸铵(B)为流动相,梯度洗脱程序为:0min,60∶40;2min,60∶40;5min,90∶10;8min,90∶10;9min,60∶40;10min,60∶40。检测波长为280nm,流速为0.25mL.min-1,柱温为40℃。结果在该色谱条件下,BHA和BHT与维生素C峰均能良好分离。BHA的检出限为0.5ng;质量浓度在0.203 5～50.88μg.mL-1范围内与峰面积呈良好的线性关系,相关系数r=0.999 9;回收率为98.3%,RSD为1.0%。BHT的检出限为0.5ng;质量浓度在0.211 4～52.84μg.mL-1范围内与峰面积呈良好的线性关系,相关系数r=0.999 9;回收率为97.2%,RSD为0.5%。结论该方法快速、专属、灵敏度高,并且节能环保。     

Pharmacokinetics of loxiglumide after single intravenous or oral doses in man

Loxiglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5-oxo-pentanoic acid, CR 1505) was given intravenously to 8 male healthy volunteers in a single dose of 2 mg/kg body weight (b.w.) or orally in a single dose of 5 mg/kg b.w. Loxiglumide was measured in plasma and in urine by HPLC during 48 h following the administration. After i.v. infusion the plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = 43.791 x e-2.652 x h + 2.657 x e-0.139 x h. In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the i.v. administration the urinary excretion of loxiglumide and of its metabolites accounted for 11.13% of the administered dose. After oral administration loxiglumide appeared in plasma with a lag time of 14 min, reached the peak 34 min after administration, being eliminated with an initial fast and a terminal slow elimination rate. The plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = -46.72 x e-8.765 x (h-0.23) + 40.660 x e-1.383 x (h-0.23) + 6.057 x e-0.120 x (h-0.23). In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the oral administration the excretion of loxiglumide and of its metabolites accounted for 7.67% of the administered dose. The absolute bioavailability of loxiglumide was calculated comparing the AUC(0-inf) found after oral and after i.v. administration and was estimated as 0.967, with p = 0.05 fiducial limit of 0.656-1.278.     

Blood and plasma concentrations of butalbital following single oral doses in man

Blood and plasma concentrations of butalbital (from Fiorinal) were determined in a small group of healthy volunteers after single oral doses of 100 mg of butalbital. Butalbital was quantitated by high-performance liquid chromatography with ultraviolet detection. Typical blood concentrations of butalbital peaked at 2.1 mg/L and declined to 1.5 mg/L at 24 h. The half-lives in blood were between 35 and 87.5 h with a mean of 61 h. Whole blood to plasma ratios were also determined.     

Enhancement of butylated hydroxytoluene-induced mouse lung damage by butylated hydroxyanisole

The phenolic antioxidant butylated hydroxytoluene (BHT) is known to produce a dose-dependent increase in mouse lung weight which is characterized by the necrosis of pulmonary type I and endothelial cells. We studied the ability of butylated hydroxyanisole (BHA) to modify BHT-induced changes in lung weight in male CD-1 mice. BHA alone had no effect on lung weight up to a dose of 500 mg/kg (sc). However, when injected 30 minutes prior to sub-threshold doses of BHT (0-250 mg/kg, ip), BHA significantly enhanced lung weight in a dose-dependent manner. The ability of BHA to enhance BHT-induced changes in lung weight was dependent on both the time and the route of administration of BHA relative to BHT. Deuteration of BHT abolished the in vivo toxicity from the combination of BHA and BHT. These results suggest that the toxicity resulting from the combination of BHA and BHT is due to the formation of BHT-quinone methide and that the role of BHA might be either to deplete some protective mechanism in the target pulmonary cells or to enhance the biotransformation of BHT into BHT-quinone methide.     

Induction of rat hepatic and intestinal glutathione S-transferases by dietary butylated hydroxyanisole.

To obtain insight into the protection mechanism of butylated hydroxyanisole (BHA), a widely used food preservative with anticarcinogenic properties, we investigated the effects of dietary BHA on rat hepatic and intestinal glutathione S-transferase (GST) enzyme activity, and GST isozyme levels. In the proximal small intestine and liver, BHA supplementation significantly increased GST enzyme activity as compared with controls (2.3- and 1.7-fold, respectively, P less than 0.05). GST class alpha and mu contents were significantly higher only in the small intestine (1.6-2.1-fold and 1.3-1.5-fold, respectively, P less than 0.05), whereas GST class pi was significantly induced in liver (4.6-fold, P less than 0.05).