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J Scatina

Publications and source records attributed to J Scatina.

15 recordsLinked to original sources
PubMed2007

Effects of ertiprotafib on hepatic cytochrome P450 and peroxisomal enzymes in rats and dogs, and in rat and human primary hepatocytes.

Ertiprotafib (ERTI) significantly increased liver weights in male and female rats, and moderately increased liver weights in male dogs after treatment for 28 days. The present study tested the hypotheses that the organ weight increases were associated with peroxisome proliferation in rats and induction of hepatic enzymes in rats and dogs, and would have limited impacts on humans. At a dosage of 200 mg kg-1 day-1, CYP4A was induced by tenfold in male rats and 2.4-fold in female rats. In male rats, CYP2B was induced by 1.2-fold and CYP3A was induced by 1.7-fold. Palmitoyl CoA oxidase was induced by 5.1-fold in male rats and 2.9-fold in female rats; carnitine acetyltransferase was induced by 10.4-fold in male rats and 5.2-fold in female rats. CYP3A, CYP4A and peroxisomal enzymes were not induced in dogs at 150/200 mg kg-1 day-1. ERTI at 50 microM markedly induced the mRNA level of CYP4A by up to fivefold in rat hepatocytes, but not in human primary hepatocytes. In conclusion, the liver weight increases observed in rats treated with ERTI appears to be due to rodent-specific peroxisome proliferation and the substantial induction of CYP4A1. ERTI is not a potent P450 inducer in dogs or in human hepatocytes. Therefore, ERTI is not expected to exert any significant effects on hepatic drug-metabolizing enzymes in humans.

Animals↗
PubMed1999

Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4.

BACKGROUND: There are large interindividual differences in CYP3A4 expression and in the metabolism of drug substrates for this enzyme. We and others have identified a polymorphism in the 5' promotor region of the CYP3A4 gene; however, its functional significance is not currently known. This study was conducted to determine whether this polymorphism plays a clinically important role in determining CYP3A4 phenotype. METHODS: An adenine (A) to guanine (G) transition was identified in the 5' promotor region of the CYP3A4 gene at position -292 (from the start codon), in a sequence motif known as the nifedipine-specific element. The frequency of this polymorphism was assessed in 802 healthy volunteers from five broadly defined racial groups. The population distribution of the G allele in these groups was as follows: white Americans (3.6%; n = 273), black Americans (54.6%, n = 186), Hispanic Americans (9.3%; n = 188), Japanese Americans (0.0%; n = 77), and Chinese Americans (0.0%; n = 78). In a subsequent study, 90 additional black Americans were genotyped, and a subset of the homozygous subjects (AA, n = 8; GG, n = 23) were given the CYP3A4 probe substrates erythromycin and nifedipine to allow genotype-phenotype comparisons to be made. RESULTS: There was no difference in the rate of CYP3A4-dependent demethylation of erythromycin (erythromycin breath test) or the pharmacokinetics of nifedipine or its CYP3A4-dependent metabolite dehydronifedipine between the two genotype groups (AA or GG). CONCLUSIONS: This promotor region polymorphism does not appear to play a major role in determining constitutive CYP3A4 expression.

Area Under Curve↗
PubMed1998

Metabolic disposition of 14C-bromfenac in healthy male volunteers.

The metabolic disposition of 14C-bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50-mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 +/- 1.8 microg x equiv/mL, which was reached 1.0 +/- 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4-day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0- to 24-hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an alpha-keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.

Adolescent↗
PubMed1998

Isolation and identification of bromfenac glucoside from rat bile.

Bromfenac (Duract(R)), a drug approved for pain, was expected to be metabolized by the rat to an acyl glucuronide, a metabolite formed with most compounds of similar structure. During the investigation of metabolite profiles in rat bile following administration of 1 mg/kg iv doses of 14C-bromfenac, an acid-labile metabolite was found that degraded to form 14C-bromfenac. Isolation and characterization of this metabolite indicated that it is an unusual conjugate, bromfenac N-glucoside.

Analgesics↗
PubMed1997

Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.

AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.

1-Naphthylamine↗
PubMed1996

Determination of 17 alpha-dihydroequilenin in rat, rabbit and monkey plasma by high-performance liquid chromatography with fluorimetric detection.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection for the determination of total (unconjugated and conjugated) 17 alpha-dihydroequilenin in male and female rat, female rabbit and male and female rhesus monkey plasma is described here. Plasma sample preparation involved hydrolysis with enzyme (Glusulase), addition of internal standard (14 beta-equilenin) and solvent extraction. The extracts were chromatographed on a C6, 5-microns reversed-phase HPLC column and detection was accomplished with a fluorescence detector operated at an excitation wavelength of 210 nm and an emission wavelength of 370 nm. The assay was linear over a range of 2.5 to 100 ng/ml in male and female rat plasma, and 5 to 500 ng/ml in female rabbit and male and female monkey plasma. The method was specific, accurate and reproducible (percent differences < 14.5; coefficients of variation < 9.5%) in all matrices examined. The applicability of this method was successfully tested by quantifying total plasma concentrations of 17 alpha-dihydroequilenin in ovariectomized female rats, ovariectomized female rabbits and a normal female rhesus monkey receiving 2.0, 8.3 and 0.1 mg/kg, respectively, of 17 alpha-dihydroequilenin sulfate intragastrically.

Animals↗
PubMed1996

[14C]7-ethoxycoumarin metabolism by precision-cut rat hepatic slices.

The metabolism of [14C]7-ethoxycoumarin ([14C]7-EC) has been studied in rat liver slice cultures in vitro by using a direct radiometric high-pressure liquid chromatography method. [14C]7-EC was extensively biotransformed in these incubations to 7-hydroxycoumarin (7-OHC), 7-hydroxycoumarin glucuronide, and 7-hydroxycoumarin sulfate, as well as to a large number of previously unrecognized metabolites, the majority of which are sulfate conjugates. The liver slice [14C]7-EC metabolite profile was also very complex and seemed to be qualitatively similar to the medium metabolite profile. Quantitative comparisons, however, demonstrated that there was approximately two to five times more 7-OHC in the liver slice than in the medium, whereas 7-hydroxycoumarin sulfate, the most abundant metabolite in the medium, was present only at low levels in the liver slice. These data demonstrate that 7-OHC levels are considerably underestimated when only levels in the medium are considered. Total metabolite levels were approximately equal in the medium and liver slice after a 2-hr incubation, with considerably higher total metabolite levels present in the medium at the end of the incubation period (8 hr). Additional studies are needed to identify the structures of the previously unrecognized metabolites observed in this study and the enzymes responsible for their formation, as well as studies to define the metabolism of [14C]7-EC in other in vitro models by using tissue from humans and other animal species.

Animals↗
PubMed1992

The disposition of venlafaxine enantiomers in dogs, rats, and humans receiving venlafaxine.

A stereospecific high-performance liquid chromatographic (HPLC) method was developed for the quantitation of the enantiomers of venlafaxine, an antidepressant, in dog, rat, and human plasma. The procedure involves derivatization of venlafaxine with the chiral reagent, (+)-S-naproxen chloride, and a postderivatization procedure. The method was linear in the range of 50 to 5,000 ng of each enantiomer per ml of plasma. No interference by endogenous substances or known metabolites of venlafaxine occurred. Studies to characterize the disposition of the enantiomers of venlafaxine were conducted in dog, rat, and human, following oral administration of venlafaxine. The Cmax, area under the curve (AUC) and (S)/(R) concentration ratios of the (R)- and (S)-enantiomers were compared. In rats, the mean plasma ratio of (S)-venlafaxine to that of (R)-venlafaxine over 0.5 to 6.0 h varied from 2.97 to 8.50 with a mean value of 5.51 +/- 2.45. The Cmax, AUC0-infinity, and t 1/2 values of the (R)- and (S)-enantiomers in dogs were not significantly different from one another (P greater than 0.1). The mean ratios [(S)/(R)] of enantiomers of venlafaxine in human over a 2 to 6 h interval ranged from 1.33 to 1.35 with an overall ratio of 1.34 +/- 0.26 (n = 12). These ratios of the enantiomers [(S)/(R)] were not statistically different from unity (P greater than 0.1) indicating that the disposition of venlafaxine enantiomers in humans is not stereoselective and is more similar to that in dogs than that in rats.

Adult↗
PubMed1986

Etodolac kinetics in the elderly.

The effects of age and chronic dosing on the pharmacokinetics of the anti-inflammatory drug etodolac were evaluated in healthy young subjects, healthy elderly subjects, and elderly patients with osteoarthritis. After either single or chronic (7 days) dosing, both the healthy elderly subjects and the elderly patients with osteoarthritis had values for etodolac peak concentration, time to reach peak concentration, the AUC from 0 to 24 hours, elimination t1/2, and free fraction that did not differ significantly from those in the young (control) subjects. Despite the expected increases in the peak concentration and AUC from 0 to 24 hours for all groups after chronic dosing, there were no changes in etodolac free fraction, time to peak concentration, or t1/2. Because significant accumulation of etodolac was not observed in our elderly participants, adjustment of dosage when elderly subjects receive etodolac therapy is not indicated.

Absorption↗
PubMed1985

The effect of Alcide, a new antimicrobial drug, on rat blood glutathione and erythrocyte osmotic fragility, in vitro.

Alcide is an antimicrobial drug which has been demonstrated to kill a variety of common pathogenic bacteria as well as fungi, in vitro. This agent is supplied in liquid and gel forms and consists of two parts, one of which contains sodium chlorite, while the other contains lactic acid as the active ingredients. Mixing of the two parts prior to use produces chlorine dioxide (ClO2), a strong oxidizing agent. A dose-dependent decrease in glutathione content and erythrocyte osmotic fragility occurred after incubation of whole blood with Alcide. Glutathione concentration and erythrocyte osmotic fragility approached the control values after 240 min of incubation with Alcide containing 1 mM NaClO2. The addition of exogenous glutathione (50 mg 100 ml-1) or glutathione reductase and NADPH to rat blood in the presence of Alcide returned erythrocyte osmotic fragility to control values. Treatment of rat blood with Alcide did not change glutathione reductase or glutathione peroxidase activities after 1 h of incubation.

Animals↗
PubMed1985

The inhibitory effect of Alcide, an antimicrobial drug, on protein synthesis in Escherichia coli.

Alcide, a broad-spectrum antimicrobial drug, has been shown to kill a wide range of common pathogenic bacteria as well as fungi, in vitro. This agent consists of Part A and Part B which contain sodium chlorite and lactic acid as the active ingredients, respectively. The mixing of these two parts immediately prior to use results in the formation of chlorine dioxide (ClO2), a potent germicidal compound. Exposure of exponentially growing E. coli cells to Alcide resulted in a rapid inhibition of growth as well as loss of viability. Alcide inhibited DNA, RNA, and protein synthesis; however, RNA and protein synthesis were affected at much lower concentrations. The accumulation of the amino acid analog amino-isobutyric acid into growing cultures of E. coli was only partially impaired by Alcide. Cell-free protein synthesis using an RNA directed system was inhibited by Alcide and this effect was lessened in the presence of mercaptoethanol. Higher concentrations of Alcide (1 mM) oxidized 25% of the methionine to methionine sulfoxide. Aminoacylation of E. coli bulk tRNA was decreased in vitro and the aminoacylation of tRNAfMet was particularly sensitive to Alcide.

Aminoisobutyric Acids↗
PubMed1984

Pharmacodynamics of alcide, a new antimicrobial compound, in rat and rabbit.

Alcide is a germicidal preparation which has been shown to kill a wide range of common pathogenic bacteria as well as fungi, in vitro. This preparation is composed of Part A and Part B which contains sodium chlorite (NaClO2) and lactic acid as the active ingredients, respectively. The two parts are combined in equal volumes immediately prior to application resulting in the formation of chlorine dioxide (ClO2). Alcide gel was applied to the shaven backs of 18 female Sprague-Dawley rats in a 2.0-g/kg dose by combining 1 g of each part immediately prior to administration. This dose was applied for a period of 10 days to reach a steady state. On the 11th day, 36Cl-labeled Alcide gel, which contained Na36ClO2 in Part A, was administered to the animals in a 0.6-g dose (2.0 g/kg) containing 0.1 microCi. The half-life for 36Cl absorption was 22.1 hr while the elimination half-life was 64.0 hr. 36Cl was excreted by the kidneys with chloride (Cl-) and chlorite as the metabolites. Ninety-six hours after Alcide administration, radioactivity was highest in whole blood and lowest in fat. In a 90-day subchronic dermal toxicity study in rabbits, exposure to Alcide gel resulted in decreased glutathione concentrations in blood of the group receiving 2.0 g/kg Alcide as well as in the placebo gel group which received the same dose of gel.

Animals↗
PubMed1983

Pharmacokinetics of Alcide, a germicidal compound in rat.

Alcide is a germicidal compound which is currently being used as a liquid sterilizer. This agent has the ability to kill a wide range of bacteria, viruses and fungi in vitro within 1 min. The active ingredients in this sterilizer are sodium chlorite and lactic acid. The kinetics of 36Cl-labelled liquid Alcide were studied in rats. After oral administration, the peak plasma level was obtained in 8 h. The half life for 36Cl absorption from plasma was 8.03 h, corresponding to a rate constant of 0.086 h-1, while the half life for 36Cl elimination from plasma was 48.02 h, corresponding to a rate constant of 0.014 h-1. At 144 h, radioactivity was highest in plasma followed by lung, kidney, skin, bone marrow, stomach, ovary, duodenum, ileum, spleen, fat, brain, liver and carcass. The greatest amount of activity in whole blood was present in plasma. Subcellular distribution revealed that 85% of the activity in the liver homogenate resided in the cytosol. Seventy per cent of total activity in plasma was located in the trichloroacetic acid (TCA) supernant, with 30% bound to the precipitated protein fraction. Urinary excretion accounted for most of the 36Cl eliminated. Radioactivity was excreted as chloride and chlorite in urine.

Animals↗