PubMed Health⌕ Search

Biomedical subjects

M Boroujerdi

Publications and source records attributed to M Boroujerdi.

At least 19 recordsLinked to original sources
PubMed2005

Decline in, and lack of difference between, average birth weights among African and Portuguese babies in Portugal.

BACKGROUND: In preliminary data in Portugal, we found that African babies of migrant mothers were heavier than White Portuguese babies born in Lisbon. We investigate whether this pattern is replicated in the national data, and in addition the trends in birth weight in these groups. METHODS DESIGN AND SETTING: Births registered between 1995 and 2002 classified by reported nationality of mothers. PARTICIPANTS: 849,595 Portuguese births ('Portuguese' nationality, predominantly of European descent) and 22,463 African births ('Angola', 'Cape Verde', or 'Guinea Bissau, Republic of Guinea or Equatorial Guinea' nationality, predominantly of African origin). RESULTS: Among Portuguese births, there was a decline in births to teenaged mothers and an increase to mothers aged >or=35 years, with >9 years of education or in a non-manual class, but among African births there was an increase in births to teenaged mothers and a decline to mothers from advantaged socioeconomic backgrounds. Using the Wilcox-Russell method, overall mean birth weights of term Portuguese (3,303, SD 424 g) and African (3297, SD 441 g) babies were not different but the percentage of small preterm births was higher among African (4.7%) than among Portuguese (2.9%) births. Between 1995 and 2002, mean birth weight of term Portuguese babies declined by 58 g (3,334-3,276 g) and of African babies by 57 g (3,341-3,284 g). The left shift of the birth weight distributions was independent of maternal age, parity, and social factors among Portuguese babies, but among African babies the decrease appeared to be associated with socioeconomic advantage. CONCLUSION: There has been a downward trend in birth weights in Portugal among both Portuguese and African term births, but average birth weights of the two groups were similar.

Adolescent↗
PubMed2001

Changes in non-22-kilodalton (kDa) isoforms of growth hormone (GH) after administration of 22-kDa recombinant human GH in trained adult males.

GH is being used by elite athletes to enhance sporting performance. To examine the hypothesis that exogenous 22-kDa recombinant human GH (rhGH) administration could be detected through suppression of non-22-kDa isoforms of GH, we studied seventeen aerobically trained males (age, 26.9 +/- 1.5 yr) randomized to rhGH or placebo treatment (0.15 IU/kg/day for 1 week). Subjects were studied at rest and in response to exercise (cycle-ergometry at 65% of maximal work capacity for 20 min). Serum was assayed for total GH (Pharmacia IRMA and pituitary GH), 22-kDa GH (2 different 2-site monoclonal immunoassays), non-22-kDa GH (22-kDa GH-exclusion assay), 20-kDa GH, and immunofunctional GH. In the study, 3 h after the last dose of rhGH, total and 22-kDa GH concentrations were elevated, reflecting exogenous 22-kDa GH. Non-22-kDa and 20-kDa GH levels were suppressed. Regression of non-22-kDa or 20-kDa GH against total or 22-kDa GH produced clear separation of treatment groups. In identical exercise studies repeated between 24 and 96 h after cessation of treatment, the magnitude of the responses of all GH isoforms was suppressed (P < 0.01), but the relative proportions were similar to those before treatment. We conclude: 1) supraphysiological doses of rhGH in trained adult males suppressed exercise-stimulated endogenous circulating isoforms of GH for up to 4 days; 2) the clearest separation of treatment groups required the simultaneous presence of high exogenous 22-kDa GH and suppressed 20-kDa or non-22-kDa GH concentrations; and 3) these methods may prove useful in detecting rhGH abuse in athletes.

Adult↗
PubMed2001

Contradistinction between doxorubicin and epirubicin: in-vitro interaction with blood components.

The molecular structure and anti-tumour activity of doxorubicin and epirubicin are similar. However, the incidence of their cardiotoxicity occurs at different cumulative dose concentrations. The purpose of this study was to investigate the in-vitro interaction of these two drugs with different blood components, namely intact erythrocytes, haemoglobin and erythrocyte ghosts. Plasma protein binding was also evaluated. The intended goal was to identify the most relevant samples among total blood, plasma or blood cells for pharmacokinetic analysis. The methodology involved the incubation of each of the blood components (the intact erythrocytes, erythrocyte ghosts, haemoglobin and plasma proteins) at physiological pH and temperature with different concentrations of each drug, followed by measurement by HPLC and fluorometry at excitation and emission wavelengths of 480 and 580 nm, respectively. The results indicated that the binding of doxorubicin and epirubicin to plasma proteins, erythrocyte ghosts and intact erythrocytes was essentially the same. However, the binding of both compounds to intact erythrocytes was significantly different from erythrocyte ghosts, which indicates that haemoglobin plays an important role in the binding to and uptake by erythrocytes. The isotherms of binding to haemoglobin revealed that the maximum binding of doxorubicin was approximately 0.42 microg mg(-1) haemoglobin; for epirubicin this value was ten times greater than for doxorubicin. The Scatchard plot of binding of both drugs to haemoglobin exhibited two distinct binding sites for each drug. The constant of association of high affinity and low capacity binding sites was significantly greater for epirubicin, whereas the constant of association of low affinity and high capacity binding sites was significantly higher for doxorubicin. The number of high affinity binding sites per mg of haemoglobin was estimated to be 0.072 for doxorubcin and 0.030 for epirubicin. The number of low affinity binding sites was significantly greater for epirubicin (1.963) than for doxorubicin (0.305). Since the combined number of binding sites for epirubicin was more than doxorubicin, and the total uptake by erythrocytes remained the same for both drugs, it was concluded that epirubicin, being a more lipophilic compound, may diffuse more freely into the cells. Therefore, it binds more to haemoglobin, whereas doxorubicin remains more adsorbed on the surface of the cells due to its self-association property. It was concluded that the interaction of both drugs with erythrocytes, although it appears to be similar, is significantly different due to the interaction with haemoglobin. The difference in this interaction is expected to influence the disposition of both drugs in-vivo.

Antibiotics, Antineoplastic↗
PubMed2001

Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in rats.

There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg(-1) per week) or as a single dose injection (20 mg kg(-1)). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameterto correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin.

Animals↗
PubMed2000

Interaction of dexrazoxane with red blood cells and hemoglobin alters pharmacokinetics of doxorubicin.

PURPOSE: The mechanism of the cardioprotective action of dexrazoxane against doxorubicin cardiotoxicity is not fully understood. It has been suggested that its hydrolysis product, ICRF-198, chelates and removes free iron and iron associated with doxorubiciniron complex and, therefore, prevents the formation of free radical, lipid peroxidation and cardiotoxicity. Dexrazoxane is also known to inhibit topoisomerase II, to prevent the inactivation of cytochrome c oxidase by Fe3+ -doxorubicin and to increase the levels of transferrin receptor (trf-rec) mRNA and cellular iron uptake. This sequestration of iron and its effect on cellular iron homeostasis may also contribute to its protective effect against doxorubicin cardiotoxicity. The present project was designed to investigate the interaction of dexrazoxane with hemoglobin and red blood cells and the subsequent effect on the pharmacokinetics and toxicodynamics of doxorubicin. METHODS: In an in vitro investigation the binding of doxorubicin (0.5-25 microg/ml) to red blood cells, erythrocyte ghosts and hemoglobin in the presence of dexrazoxane was evaluated. In an in vivo study female Sprague Dawley rats were pretreated with 100 mg/kg of dexrazoxane by intravenous injection 1 h before the injection of 14C-doxorubicin (specific activity 0.4 microCi/mg, 10 mg/kg). The time-course of doxorubicin associated with blood cells and plasma was evaluated with simultaneous characterization of doxorubicin and its metabolites in the bile and urine. The serum concentration ofendothelin was measured as a biomarker of cardiotoxicity in separate groups of animals. RESULTS: The in vitro data indicated that dexrazoxane inhibited the binding of DOX to red blood cells in a concentration-dependent manner. At 1 microg/ml it reduced the binding of doxorubicin to red blood cells by about 30% and at 100 microg/ml by about 60%. It had no effect on the association of doxorubicin with erythrocyte ghosts. The investigation of binding of doxorubicin to hemoglobin revealed the existence of two distinct binding sites and dexrazoxane reduced the association constant of doxorubicin with the low-affinity and high-capacity class of binding sites significantly. The pharmacokinetic analysis showed that pretreatment with dexrazoxane (100 mg/ kg) reduced the area under plasma concentration-time curve of doxorubicin, its mean residence time and plasma clearance significantly. Similar reductions were also shown with the pharmacokinetic analysis of doxorubicin associated with blood cells. The biliary and urinary elimination of unchanged doxorubicin increased significantly. The pretreatment reduced the serum concentration of endothelin from about 20 ng/ml to about 12 ng/ ml. The per cent of this reduction was proportional to the reduction in the AUC of blood cells. CONCLUSION: The cardioprotective effect of dexrazoxane is due, in part, to its interaction with hemoglobin and red blood cells and this interaction modifies the pharmacokinetics of DOX.

Animals↗
PubMed2000

Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats.

UNLABELLED: The purpose of this study was to examine the effect of tamoxifen pretreatment on the metabolism and pharmacokinetics of doxorubicin. We tested the hypothesis that the pretreatment would counteract the side effects of doxorubicin and modify the disposition of the drug. The concentration-time profiles of doxorubicin in plasma and blood cells were determined in conjunction with the cumulative amount of renal and hepatobiliary elimination of unchanged drug and metabolites following a 10-day tamoxifen pretreatment at a dose of 1 mg/kg per day. Furthermore, under the same experimental protocol the serum concentration-time profile of endothelin was determined as a biomarker of toxicity. METHODS: Female Sprague Dawley rats (225-275 g). pretreated orally for 10 days with corn oil or tamoxifen in corn oil (1 mg/kg per day), received 14C-doxorubicin (specific activity 0.4 microCi/mg, 10 mg/kg) intravenously. Plasma, blood cells, bile and urine were collected periodically and analyzed for doxorubicin and its metabolites. Four other groups of animals received the same pretreatment and non-labeled doxorubicin. Their serum samples were analyzed for endothelin. Two additional groups were also used to examine the effect of tamoxifen on the in vitro metabolism of doxorubicin by the cytosolic enzyme aldo-keto reductase. RESULTS: Tamoxifen pretreatment reduced the total protein of the cytosolic fraction by 50% and reduced the formation of doxorubicinol both in vitro and in vivo. The pretreatment resulted in a notable increase in the area under plasma and blood cells concentration-time curves of doxorubicin and a significant reduction in mean residence time, apparent volume of distribution and serum endothelin levels. CONCLUSIONS: We attributed the increase in the area under the curves of plasma and blood cells following tamoxifen pretreatment to a reduction in the uptake of doxorubicin by peripheral tissues. This conclusion was consistent with the reduction in the volume of distribution of plasma, mean residence time and higher availability of the parent compound for excretion. An interesting observation was that the increase in concentration of doxorubicin in plasma was not concomitant with an increase in concentration of doxorubicinol. The levels of this toxic metabolite and its corresponding biliary rate constant were reduced by approximately 50%. The results demonstrate that tamoxifen, in addition to being a modulator of P-glycoprotein and counteracting the effects of doxorubicin at the cellular level, also alters the metabolic profile of doxorubicin either by inhibiting the formation of the toxic metabolite doxorubicinol or by reducing the enzyme responsible for the biotransformation. The change in metabolism may well be a contributing factor to reduction of serum endothelin levels.

Animals↗
PubMed1999

Inhibition of aldo-keto reductases by phenobarbital alters metabolism, pharmacokinetics and toxicity of doxorubicin in rats.

Doxorubicin is an effective anticancer agent that is limited by numerous adverse effects, cardiotoxicity causing the most concern. Its alcohol metabolite, doxorubicinol, and free radicals have been implicated in the aetiology of this toxicity. This study was based on the premise that inhibition of aldo-keto reductases would improve the efficacy of doxorubicin by reducing its toxic metabolites and modifying its pharmacokinetics. We assessed the effect of in-vitro inhibition of aldo-keto reductases on the metabolism of doxorubicin in cytosolic fractions of heart and liver of rats in the presence of Na-phenobarbital. The inhibition was confirmed by a significant reduction in the formation of doxorubicinol. The results of the in-vitro study were further evaluated in-vivo. The concentrations of doxorubicin in plasma, bile and urine and its major metabolites in bile and urine were measured in Na-phenobarbital-pretreated rats. Each rat received 100 mg kg(-1)/day intraperitoneal injection of sodium phenobarbital for three days followed by a single intravenous dose of 10 mg kg(-1) [14C-14]doxorubicin (sp. act. 0.2 microCi mg(-1)) on the fourth day. The levels of drug in all biological samples were measured by HPLC. The pretreatment resulted in an increase in biological half-life (5.8 +/- 1.5 vs 3.7 +/- 0.93 h control group, P < 0.05) and area under plasma concentration-time curve (19.6 +/- 1.7 vs 14.65 +/- 1.68 mg h L(-1) control group, P < 0.05). The cumulative amount of doxorubicinol in the bile and urine of pretreated animals was reduced significantly. In terms of % dose, the amount in the bile declined from 4.2 +/- 0.8% in control to 2.4 +/- 0.3% and in urine from 0.18 +/- 0.08% to 0.12 +/- 0.07%. There were no significant changes in doxorubicin aglycone and doxorubicinol aglycone. Serum creatine kinase levels were measured as a biomarker of damage to cardiac muscle. The area under creatine kinase level-time curve was reduced by approximately 50% in phenobarbital-pretreated animals. The results indicate that the inhibition of aldo-keto reductase could provide a useful approach to improve the safety of doxorubicin by reducing its alcohol metabolite. Furthermore, if the reduction in the area under the serum creatine kinase-time curve represents a reduced damage to heart muscle, it can be concluded that doxorubicinol plays an important role in this injury.

Alcohol Oxidoreductases↗
PubMed1998

Investigation of the enterohepatic recirculation of Adriamycin and its metabolites by a linked-rat model.

We investigated the possible role of enterohepatic recirculation in prolongation of the half-life of elimination for Adriamycin, a commonly prescribed anticancer agent. We sought to determine whether enterohepatic recirculation of Adriamycin and its metabolites occurs using a linked-rat model. Two rats, a donor and a receiver, were linked via a catheter from the bile duct of the donor rat to the duodenum of the receiver. Control experiments were conducted with intact rats (without a bile duct cannula, control A) in order to estimate the half-life of elimination and with bile duct-cannulated rats (control B) to determine the amounts of Adriamycin and its metabolites in the bile. [14C-14]-Adriamycin was injected intravenously via the femoral vein to control A, control B and donor rats. The biological half-life of Adriamycin in the intact rats (control A, 10 h) was significantly higher than in the bile-duct-cannulated rats (control B, 4 h). The cumulative amount of Adriamycin and its metabolites excreted in the urine of the control A rats was also greater than from control B rats, indicating higher levels of the drug in their systemic circulation. Biological samples (bile, urine, plasma, blood cells and the major organs heart, liver and kidney) of the receivers contained significant amounts of Adriamycin and its metabolites. The total radioactivity recovered in the bile of the receivers accounted for 0.1% to 8% of the Adriamycin dose that was administered to the donors. Adriamycin and its metabolites appeared there only after a lag time that was consistent among all the receivers. Doxorubicinol aglycone was the major metabolite found in the bile and urine of the receivers. Low but constant levels of radioactivity were also detected in the plasma and blood cells of the receivers. The presence of unchanged Adriamycin in the bile and urine of the receivers suggested absorption of the parent drug from the intestine of the receivers. Overall, we estimated that about 22% of the dose injected to the donors was absorbed from the intestine of the receivers. Taken together, these findings clearly demonstrate a significant role for enterohepatic recirculation of Adriamycin and its metabolites, which may contribute to the ability of these compounds to induce cumulative cardiac damage and/or to increase the efficacy of Adriamycin.

Animals↗
PubMed1996

Pharmacokinetic-toxicodynamic relationships of adriamycin in rat: prediction of butylated hydroxyanisole-mediated reduction in anthracycline cardiotoxicity.

Adriamycin, an anthracycline antibiotic, has broad antitumour activity with cumulative dose-dependent cardiotoxicity as its major side effect. This study was designed to quantify and correlate the cardiotoxicity and pharmacokinetics of adriamycin in-vivo in rat. The influence of antioxidant (butylated hydroxyanisole, BHA) co-therapy on the cardiotoxicity and disposition of adriamycin was also studied. Cardiotoxicity was estimated by serially measuring serum creatine kinase (CK) levels after intravenous administration of adriamycin (4, 10, 20, and 30 mg kg-1) and adriamycin-BHA (10 and 30 mg kg-1 each). Peak serum CK concentrations (CKmax) and area under serum CK-time curves (AUCCK) were used as cardiotoxicity indices. Pharmacokinetic studies were undertaken by sampling plasma and urine from distinct groups of rats treated with [14C]adriamycin (at the above doses) and [14C]adriamycin-BHA (10 mg kg-1 each). Co-administration of BHA resulted in a significant reduction in CKmax and also resulted in a significant reduction in the renal clearance of adriamycin which was fully compensated by an increase in its metabolic clearance. A linear increase in the area under the plasma adriamycin concentration-time curves (AUC) with increasing adriamycin doses suggested dose-independent disposition of the drug. The most significant pharmacokinetic-toxicodynamic relationships included: CKmax = 2.25 x 10(2) exp (4 x 10(-4) AUC), r2 = 0.941, P < 0.05 and AUCCK = 1.3 x 10(4) exp(2 x 10(-4) AUC0-tmax), r2 = 0.918, P < 0.05 where, AUC0-tmax is the area under the adriamycin concentration-time curve from time 0 to the time of the peak CK level. The results strongly indicate that the drug-induced cardiotoxicity is initiated shortly after dosing when drug concentrations are high and accumulates with continued exposure. The predicted cardiotoxic indices, obtained from altered adriamycin pharmacokinetic parameters as a result of BHA co-therapy, compared favourably with the observed values.

Animals↗
PubMed1996

Protective effect of butylated hydroxyanisole on adriamycin-induced cardiotoxicity.

Adriamycin has a wide spectrum of antitumour activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen free radicals. The objective of the present study was to investigate the influence of the antioxidant, butylated hydroxyanisole co-therapy on the cardiotoxicity of adriamycin, in-vivo. The aqueous solubility of butylated hydroxyanisole was enhanced by inclusion complex formation with hydroxypropyl-beta-cyclodextrin. The extent of drug-induced myocardial damage in rats was assessed using intravenous 111In-labelled antimyosin Fab and chronological changes in serum creatine kinase levels. There was a dose-related increase in myocardial antimyosin uptake in rats, which reached a plateau at an adriamycin dose of 10 mg kg-1. The antimyosin uptake at this dose (% dose g-1 = 0.1942 +/- 0.0150, n = 8) was significantly reduced by co-administration of butylated hydroxyanisole with adriamycin (10 mg kg-1 of each) to 0.1462 +/- 0.0116 (n = 5, P < 0.05). Assessment of cardiotoxicity in the rats was also performed by measuring serial changes in serum creatine kinase levels. Increasing doses of adriamycin caused an increase in serum creatine kinase levels with peak values obtained between 2 and 8 h after dosing. These values decreased upon co-administration of butylated hydroxyanisole with adriamycin at 10 mg kg-1, each and 30 mg kg-1 each by 29 and 41%, respectively. On the other hand, butylated hydroxyanisole did not inhibit the tumouricidal activity of adriamycin as investigated in-vitro using the NMU rat mammary adenocarcinoma cell-line. The significant reduction in anthracycline cardiotoxicity by butylated hydroxyanisole coadministration may result from its scavenging action on adriamycin-mediated free-radical formation or its enhancement of activity of enzymes involved in the metabolism of adriamycin.

Animals↗
PubMed1995

Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs.

Insulin analogues with relatively greater effect on hepatic glucose production than peripheral glucose disposal could offer a more physiological approach to the treatment of diabetes mellitus. The fact that proinsulin exhibits this property to a minor degree may suggest that analogues with increased molecular size may be less able than insulin to obtain access to peripheral receptor sites. Covalent insulin dimers have previously been shown to possess lower hypoglycaemic potencies than predicted by their in vivo receptor binding affinities. Reduced rates of diffusion to peripheral target tissues might be an explanation for the lower in vivo potency compared to insulin. To test the relative hepatic and peripheral effects of covalent insulin dimers, glucose clamp procedures with D-[3-3H]glucose tracer infusions were used in anaesthetised greyhounds to establish dose-response curves for rates of hepatic glucose production and glucose disposal with insulin, N alpha B1, N alpha B'1,-suberoyl-insulin dimer, and N epsilon B29, N epsilon B'29,-suberoyl-insulin dimer. With N alpha B1, N alpha B'1,-suberoyl-insulin dimer molar potencies relative to insulin were 68%, (34-133) (mean and 95% fiducial limits), for inhibition of hepatic glucose production and 14.7%, (10.3-20.9) for glucose disposal. With N epsilon B29,N epsilon B'29,-suberoyl-insulin dimer potencies were 75%, (31-184) and 2.5%. (1.5-4.3), for inhibition of hepatic glucose production and for glucose disposal, respectively. The demonstration that both dimers exhibit a significantly greater effect on glucose production than on glucose disposal supports the suggestion that analogues with increased molecular size may exhibit reduced ability to gain access to peripheral target cells.

Analysis of Variance↗
PubMed1988

Effect of cimetidine on in vivo formation of adducts between metabolites of benzo(a)pyrene and DNA.

Cimetidine has been reported to interact with liver microsomal enzymes, specifically, the cytochrome P-450 and P-448. Consequently cimetidine has the potential to impair the metabolism of compounds that undergo oxidative metabolism. The present study was designed to examine the benzo(a)pyrene-DNA adducts in the lungs and liver of mice after pretreatment with cimetidine. Male A/J mice received an i.p. dose of 40 mg/kg cimetidine followed by an oral dose of 5 micro mol/kg of [G-3H]BP 30 minutes apart. Control group received equal p.o. dose of BP. Animals (10 per group) were killed by cervical dislocation at 1h and 6h. The lungs and liver were removed and homogenized. DNA was then extracted, digested enzymatically to deoxyribonucleosides, and the adducts were analyzed by HPLC. The results showed that the percent of the adducts was reduced significantly.

Animals↗
PubMed1987

BHA (2(3)-tert-butyl-4-hydroxyanisole)-mediated modulation of acetaminophen phase II metabolism in vivo in Fisher 344 rats.

Adult male Fisher 344 rats (190-220 g), were given an intravenous dose (10 mg/rat) of BHA. Pretreated and control rats received an intravenous dose of [G-3H] acetaminophen (25 mg/rat). Bile was collected prior to dosing and for 5-6 hours after dosing at varying time intervals. Separate aliquots of 0.2 ml were incubated with beta-glucuronidase and sulfatase, respectively. These incubation mixtures were then extracted and analyzed by reverse phase HPLC. In all cases control animals showed a greater deceleration in the biliary excretion of the water soluble metabolites when compared with pretreated animals. Increases in both glucuronide and sulfate elimination processes are assumed to be contributory, in part, to the overall effect of BHA on acetaminophen metabolism.

Acetaminophen↗
PubMed1986

A nonlinear tissue-binding model for creatine: estimation of creatine turnover time and creatinine production rate.

Intravenous bolus injections of 14C-labeled creatine were made in rabbits. Plasma and urine concentrations were measured. Plasma specific activity and urinary cumulative radioactivity data were examined by several means including the use of NONLIN. Utilization of urine and blood data suggested that a nonlinear model was more appropriate. The selected model has two nonlinear binding parameters and an elimination rate constant. The creatine turnover time was calculated to be about 22 minutes. The model allows the predication of creatine production rate that is in general agreement with the literature values.

Animals↗
PubMed1984

Protective action of 2(3)-tert-butyl-4-hydroxyanisole (BHA) on acetaminophen-induced liver necrosis in male A/J mice.

Groups of male A/J mice were given either a regular diet or a regular diet supplemented with 1% BHA. After 10 days of feeding acetaminophen was administered intraperitoneally in amounts known to induce liver necrosis (500 mg/kg). Liver slices from the central lobe, were examined histologically for the extent of necrosis. Eight of the 17 mice treated with BHA showed no necrosis. In contrast 12 of 16 specimens from the mice treated with acetaminophen alone showed a severe centrilobular necrosis. The microsomal-mediated covalent binding of acetaminophen metabolites in-vitro was lower for microsomes from BHA pretreated mice than those from control mice. These results suggest that the ability of BHA to modify the activity of the drug metabolizing enzymes or to act as a scavenger may account for its protective action against acetaminophen-induced liver necrosis.

Acetaminophen↗
PubMed1983

Metabolism of creatinine in vivo.

Two forms of radiolabeled creatinine were used in this study, [carbonyl-14C]- and [amidino-14C]creatinine, the latter being synthesized in this laboratory. These labeled compounds were given intravenously to rabbits. Specimens of plasma, urine, feces, and selected tissues were collected. These were liquid-chromatographed and the separated components compared for radioactivity and identity. This first use of amidino-labeled creatinine revealed the metabolic conversion of small amounts of creatinine to an unidentified non-basic compound and guanidinobutyrate in normal rabbits and to guanidinopropionic acid and arginine in a rabbit that had a low creatinine clearance. A mechanism is suggested for this metabolic process. The proposed pathway may be a major route of elimination of creatinine in renal failure.

Animals↗