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M Strolin-Benedetti

Publications and source records attributed to M Strolin-Benedetti.

At least 19 recordsLinked to original sources
PubMed2005

Evaluation of pharmacokinetic interaction between cetirizine and ritonavir, an HIV-1 protease inhibitor, in healthy male volunteers.

BACKGROUND: Serious adverse effects have been observed with some non-sedative H1-antihistamines (terfenadine and astemizole) when they were associated with drugs known to inhibit their metabolism. However, this is not a class effect, and this interaction should be considered on a case-by-case basis. The aim of this study was to evaluate the potential of pharmacokinetic interaction between cetirizine and ritonavir, the most potent cytochrome P450 (CYP) inhibitor. METHODS: An open-label, single-center, one-sequence crossover pharmacokinetic study was conducted in three running periods: cetirizine (CTZ) alone, ritonavir (RTV) alone and then CTZ plus RTV. For each period, steady-state pharmacokinetics were obtained. RTV and CTZ plasma concentrations were determined using validated liquid chromatography methods. The statistical method was based on a 90% confidence interval (CI) for the ratio of population geometric means (combination/drug alone) for each drug and for each parameter [area under the plasma concentration versus time curve (AUC(0-tau,ss)), value of maximum plasma concentration (C(max,ss))] and compared to bioequivalence ranges 80-125% and 70-143% for AUC(0-tau,ss) and C(max,ss), respectively. RESULTS: Among the 17 male subjects enrolled (26.4 +/- 8.6 years), 16 completed the study (1 withdrawal after the first period). The RTV pharmacokinetic parameter values were not affected by CTZ co-treatment. With RTV, a 42% increase in the CTZ AUC(0-tau,ss) (3406 versus 4840 microgh/l, 90% CI of 128-158%), a 53% increase in the CTZ elimination half-life (7.8 h versus 11.9 h, P = 0.001), a slight increase (15%) in the CTZ apparent volume of distribution (V(d,ss)/f) (34.7 l versus 39.8 l, P = 0.035), a 29% decrease in the CTZ apparent total body clearance (49.9 ml/min versus 35.3 ml/min, P < 0.001) and bioequivalent C(max,ss) (374 microg/l versus 408 microg/l) were observed. No serious drug related adverse effects were notified. CONCLUSIONS: CTZ does not significantly affect the pharmacokinetic parameters of RTV, and the association does not, thus, require a modification of the dosage of the protease inhibitor. The increased extent of exposure to CTZ in healthy subjects, in the presence of RTV administered at high doses, remained in the same range as previously observed in the elderly or in mildly renally impaired subjects.

Adolescent↗
PubMed2000

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration.

1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 microCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 microCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 microCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 microCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.

2-Naphthylamine↗
PubMed2000

N-methyl(R)salsolinol and a neutral N-methyltransferase as pathogenic factors in Parkinson's disease.

The pathogenesis of Parkinson's disease is still an enigma. As an endogenous MPTP-like neurotoxin, N-methyl(R)salsolinol was proved to induce parkinsonism in rats and apoptosis in dopaminergic neurons. It is synthesized in the human brain by two enzymes; an (R)salsolinol synthase and an N-methyltransferase, and accumulates in the nigro-striatum in human brains. The activity of a neutral N-methyltransferase in the striatum was found to determine the level of MPP+-like 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, an oxidation product of N-methyl(R)salsolinol in the substantia nigra. The activity of this N-methyltransferase was found to increase significantly in lymphocytes prepared from parkinsonian patients. In cerebrospinal fluid from untreated parkinsonian patients, N-methyl(R)-salsolinol increases significantly. These results suggest that N-methyl(R)salsolinol and a neutral N-methyltransferase may be endogenous factors in the pathogenesis of Parkinson's disease.

Aged↗
PubMed1999

Association of cytochrome P450 induction with oxidative stress in vivo as evidenced by 3-hydroxylation of salicylate.

1. Previous studies have shown that formation of 2,3-dihydroxybenzoate (2,3-DHB) from salicylate in vivo is a sensitive and specific marker of *OH radical generation, since 2,3-DHB is formed exclusively by *OH radicals, whereas both *OH radicals and cytochrome P450 (CYP) contribute to the production of 2,5-DHB. In the present study the salicylate-hydroxylation assay was used to examine whether CYP induction by the administration of dexamethasone, phenobarbital or beta-naphthoflavone to the male rat led to oxidative stress in vivo. 2. Dexamethasone was used under conditions that induced an approximately 50-fold induction of CYP P4503A expression in liver microsomal protein. Treatment with dexamethasone caused a 17.2-fold increase in 2,3-DHB plasma concentration compared with control animals. An increase in total hydroxylated salicylate (2,3-DHB plus 2,5-DHB) of 133.5 micromol/l plasma was produced, of which--assuming that the attack by *OH in position 3 or 5 of salicylate occurs at a similar rate--10.9 micromol/l were due to *OH radical attack and 122.6 micromol/l due to metabolism by CYP. 3. Phenobarbital led to a 4.7-fold increase in 2,3-DHB plasma concentration under conditions that induced CYP P4502B and 3A. An increase in total hydroxylated salicylate of 34.3 micromol/l plasma was observed, 2.0 micromol/l due to *OH radical attack and 32.3 micromol/l due to metabolism by cytochrome P450. 4. In contrast to dexamethasone and phenobarbital, beta-naphthoflavone did not cause a significant increase in 2,3-DHB plasma concentrations. 5. SKF 525A, a mixed-function oxidase inhibitor, caused a significant reduction of mean 2,5-DHB plasma concentration by 35% (p < 0.001), whereas 2,3-DHB was not significantly reduced, indicating that in contrast to the situation after induction by dexamethasone or phenobarbital, *OH radical generation by constitutive CYP contributes only to a minor degree to total in vivo *OH radical generation. 6. This study shows for the first time, to the authors' knowledge, that induction of some (but not all) P450s is associated with the production of hydroxyl radicals in vivo.

Animals↗
PubMed1996

A model based assessment of redistribution dependent elimination and bioavailability of rifabutin.

The autoinduction characteristic of rifabutin (RIF) following multiple oral dosing was investigated via pharmacokinetic modeling. A two-compartment model with first-order absorption was fit to plasma RIF data obtained from a study conducted in healthy normal volunteers following both a single and multiple oral doses. Parameter estimates showed an elimination rate constant (k10) of about 0.12-0.14 h-1 which was independent of the single or multiple-dosing condition. The lower-than-expected drug accumulation following multiple dosing seems to suggest that prolonged dosing perturbs the linear kinetic system. However, this analysis has shown no significant changes (p > 0.05) in the rate constants describing RIF absorption, tissue distribution/redistribution, and elimination. The mean rate of drug redistribution from the tissue compartment (k21; 0.04-0.06 h-1) was twofold to threefold lower than k10, and, with a large steady-state distribution volume (Vss/F after a single dose, 1630 L), RIF elimination appears to be dependent on drug redistribution. This hypothesis was further supported by a significant correlation (p < 0.01) between RIF tissue redistribution (k21) and terminal disposition phase rate (lambda z) constants. The redistribution dependent elimination of RIF also helps explain the stability of the terminal half-life under both single and multiple-dosing paradigms. Urinary excretion of RIF and its 25-O-deacetyl metabolite totalled less than 7% of the oral dose following single dosing, and decreased to about 4% after multiple dosing. For individual patients, the decrease in urinary recovery of the 25-O-deacetyl metabolite was directly proportional to the decrease in urinary RIF recovery. In addition, both estimates of the model intercepts (A and B) were lower following multiple dosing. Further analyses revealed a linear relationship between A and B intercepts, and also between the urinary RIF recovery and the B intercept. These relationships, in conjunction with the lack of significant increase in the rate of elimination, indicate that induction of presystemic extrahepatic metabolism and/or decrease in the extent of oral absorption may be the primary causes for the lower-than-expected systemic RIF plasma levels after multiple oral dosing.

Administration, Oral↗
PubMed1996

The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers.

The effect of food on the pharmacokinetics and tolerability of cabergoline in man was investigated. For this purpose an open, randomized, single-dose study was conducted in 12 healthy male volunteers who received 1 mg cabergoline as tablets both under fasting conditions and after a breakfast containing a substantial amount of carbohydrates, fat, and proteins, in a crossover fashion. The two treatments were separated by a 4 week washout period. Plasma and urine were collected up to 336 and 168 h respectively after administration and cabergoline concentration was measured in both fluids using a validated radioimmunoassay. Tolerability assessment included haematology, blood chemistry, and urinalysis, blood pressure and heart rate measurements, and ECG. Under both fasting and fed conditions low but persistent cabergoline plasma levels were observed in the present study up to 2 weeks after drug intake, in agreement with the long-lasting prolactin-lowering activity of the drug. In subjects receiving cabergoline under fed or fasting conditions, Cmax values averaged 44 and 54 pg mL(-1), AUC(0-336 h) averaged 6392 and 5331 pg h mL(-1), Ae(0-168 h) averaged 12.7 and 11.9 micrograms, and t1/2 averaged 109.7 and 101.3 h, respectively. No statistically significant difference was found when Cmax, AUC(0-336 h), t1/2, and Ae(0-168 h) from subjects treated under fasting and fed conditions were compared. Median tmax values in subjects treated under fasting or fed conditions were identical (2.5 h). The statistical analysis applied to the parameters chosen to evaluate the variations in the blood pressure profiles observed either supine or standing did not show any significant difference between the fed and fasting conditions. Heart rate values were not significantly modified after cabergoline under either fed or fasting conditions. Laboratory evaluation showed some minor deviations from normal, which were not clinically relevant (only one subject showed an occasional and transient elevation in alkaline phosphatase which disappeared in the subsequent laboratory evaluations) and were considered for the most part not to be drug related. Eleven subjects reported adverse events (one after both treatments, five only after drug intake under fasting conditions, and five only after drug intake with food.

Adult↗
PubMed1995

Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.

Adult↗
PubMed1994

Pharmacokinetic and pharmacodynamic studies following single and multiple doses of rolafagrel, a novel inhibitor of thromboxane synthase, in normal volunteers.

The pharmacokinetics and pharmacodynamics of rolafagrel (FCE 22178), a novel thromboxane synthase inhibitor, were evaluated after single and multiple oral doses in eight healthy volunteers. After a single dose (400 mg), the drug was absorbed rapidly, peak plasma concentrations being attained within 2 h in all subjects. Elimination followed a biphasic course, with a rapid initial decline followed after 12-24 h by a late phase with a terminal half-life of about 10 h. About 100% of the administered dose could be recovered in urine within 72 h, mostly in conjugated form. During multiple dosing (400 mg t.i.d. for 5 days), steady-state conditions were approached on day 2 and AUC values over a dosing interval were similar to those observed after a single dose (72.3 vs 76.3 micrograms.ml-1.h). Pharmacokinetic parameters calculated after multiple doses were similar to those observed after a single dose (Cmax: 20.1 vs 18.2 micrograms.ml-1; tmax: 1.2 vs 1.1 h; terminal half-life: 10.9 vs 11.4 h; CL: 85.2 vs 70.4 ml.h-1.kg-1; V: 1.23 vs 1.24 l.kg-1). Platelet generation of thromboxane B2, the stable breakdown product of thromboxane A2, was inhibited by 85% at a plasma rolafagrel concentration of about 4 micrograms.ml-1, and only a small increase in inhibition was observed at higher concentrations.

Administration, Oral↗
PubMed1993

Excretion balance and urinary metabolites of the S-enantiomer of indobufen in rats and mice.

The excretion balance and urinary metabolites of the S-enantiomer of indobufen, ((S)2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a platelet aggregation inhibitor, were studied in rats and mice after oral administration. The urinary metabolic profile exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rat urine 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group accounted for almost all recovered radioactivity. Indobufen glucuronide was the major biliary metabolite in the rat, while very little indobufen glucuronide was present in the urine of intact or bile duct-cannulated rats. A marked dose-effect on the elimination and metabolism of S-indobufen was demonstrated in the rat. The recovery (% dose) of 5-hydroxyindobufen and its sulphate after the lower dose of the enantiomer (10 mg/kg) was some 2.8-fold higher compared with the higher dose of 20 mg/kg.

Animals↗
PubMed1993

Excretion balance and urinary metabolism of indobufen in rats and mice.

The excretion balance and the urinary metabolism of indobufen (+/- 2-[p-(1-oxo-2-isoindolinyl)-phenyl] butyric acid), a platelet aggregation inhibitor, has been studied in rats and mice after oral administration. The urinary metabolic profile of indobufen exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rats, 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group predominated. Comparison of these results with previous data obtained in humans indicates that the mouse, and not the rat, is the rodent species of choice to be considered in the study of this compound.

Animals↗
PubMed1993

Bioavailability of a new oral formulation of medroxyprogesterone acetate compared with the standard formulation: a single dose randomized study.

Twenty-six female patients with breast cancer participated in an open, randomized, cross-over study comparing single dose bioavailability of a recently developed oral medroxyprogesterone acetate (MPA) formulation (200 mg sachet where MPA is loaded in a polyvinylpyrrolidone cross-linked polymer, MPA/PVP) with the standard formulation (500 mg tablet). Blood tests were performed under standardized conditions for 120 h in all patients and MPA plasma concentrations determined by means of HPLC. Dose-normalized AUC(0-tz), AUC (0-infinity) and Cmax were all significantly higher for the MPA/PVP formulation than for the standard formulation. The relative bioavailability of the MPA/PVP formulation was on average three times superior to that of the standard formulation. This new MPA formulation might have important clinical implications for the treatment of hormone-sensitive cancer.

Administration, Oral↗
PubMed1992

The d-enantiomer form of indobufen totally accounts for the anti-cyclooxygenase and antiplatelet activity ex vivo and for the increase in bleeding time by indobufen in man.

Indobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean +/- S.D., 58.7 +/- 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 +/- 3% for both treatments). At 12 h inhibition was 87 +/- 6% for d-indobufen and 88 +/- 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study.

The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1988

Time-dependence and differential induction of rat and guinea pig peroxisomal beta-oxidation, palmitoyl-CoA hydrolase, cytosolic and microsomal epoxide hydrolase after treatment with hypolipidemic drugs.

Fischer-344 rats and Hartley guinea pigs received a diet containing 0.01% (w/w), 0.05% (w/w), or 0.25% (w/w) of the hypolipidemic drug fenofibrate. Rats were treated for 4, 7, 14, or 21 days, and a clear dose-dependent and weak time-dependent increase in liver/body weight ratio was observed. The specific activity of peroxisomal beta-oxidation increased linearly with time at all concentrations used. A dose-dependent increase in cEH was observed, but the activity remained constant after treatment for 7 days. Enhancement of palmitoyl-CoA hydrolase was dose-dependent, but was similar at all 4 time points investigated. In contrast to the other enzyme activities, mEH was not or only minimally (less than 1.5-fold) induced. In contrast to the rat, treatment of guinea pigs with fenofibrate for 1 week did not change liver weight or enzyme activities. Prolonged treatment of guinea pigs (4 weeks) with fenofibrate did not result in an increase in enzyme activities. This was also observed with clofibrate whereas tiadenol caused a slight increase in enzyme activities (1.5- to 2.6-fold). In contrast to the guinea pig each of the three hypolipidemic drugs led to an increase in enzyme activities in the rat liver after treatment for 1 week.

Animals↗
PubMed1987

Inhibition of cytochrome P-450-dependent oxidation reactions by MAO inhibitors in rat liver microsomes.

The inhibition of cytochrome P-450 dependent hydroxylations of bufuralol (BH) and antipyrine, and O-deethylation of 7-ethoxycoumarin (7-ECOD) by several monoamine oxidase inhibitors (MAOIs) was investigated in rat liver microsomes. According to their IC50 values, clorgyline was the most potent inhibitor while toloxatone, the only reversible MAOI in this study, was the least potent. A great variability of inhibitory potencies was found, even in the same chemical class of MAOIs. Irreversible inhibition of BH and 7-ECOD has been studied. Rapid irreversible inhibition occurred in some cases, and this could be responsible for in vivo inhibition after repeated dosing of these MAOIs.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1987

Concomitant induction of cytosolic but not microsomal epoxide hydrolase with peroxisomal beta-oxidation by various hypolipidemic compounds.

The effects of two cholesterol-lowering (probucol and 1-benzyl-imidazole), three triglyceride- and cholesterol-lowering (clofibrate, tiadenol and fenofibrate) and one triglyceride-lowering (acetylsalicylic acid) compounds on the specific activities of two lipid-metabolizing enzymes (cyanide-insensitive peroxisomal beta-oxidation and palmitoyl-CoA hydrolase) and two xenobiotic metabolizing enzymes (cytosolic (cEH) and microsomal epoxide hydrolase (mEHb] from the livers of male Fischer F-344 rats were investigated. With the exception of probucol and acetylsalicylic acid, all compounds tested caused a dose-dependent hepatomegaly. Taken on a weight basis fenofibrate was the most effective inducer, causing a 20-fold induction of peroxisomal beta-oxidation, a 13-fold induction of cEH activity and a 16-fold induction of palmitoyl-CoA hydrolase activity. The other compounds with triglyceride-lowering activity also induced cEH as well as peroxisomal beta-oxidation and palmitoyl-CoA hydrolase activity. The potency of each individual drug was similar for induction of cEH activity as compared with that of peroxisomal beta-oxidation and palmitoyl-CoA hydrolase activity, but very dissimilar for mEHb, which upon treatment with any of the triglyceride-lowering compounds was either not or only minimally (less than 1.5-fold) induced. 1-Benzylimidazole possessing exclusively cholesterol-lowering activity increased mEHb much more than either cEH or peroxisomal beta-oxidation. The absence of an enhancement of cEH activity in in vitro studies confirmed that the increase in enzyme activity by the test compounds is not caused by activation. cEH activity was also induced in the kidney but only about 2-fold by fenofibrate, tiadenol and acetylsalicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Oral absorption and concentration-effect relationship of tyramine with and without cimoxatone, a type-A specific inhibitor of monoamine oxidase.

The mechanism of increased sensitivity to oral tyramine in patients taking monoamine oxidase inhibitors was investigated by measurement of plasma norepinephrine and tyramine with a reversible, monoamine oxidase form A selective inhibitor, cimoxatone. In the first open study, the pressor activity of 80 mg oral tyramine after cimoxatone was of the order of that of 800 mg without the drug. In a second double-blind study, the equivalent tyramine dose was between 400 and 800 mg. Absorption of unmetabolized tyramine increased in the presence of cimoxatone. Peak plasma concentration of tyramine after an 80-mg dose was approximately three times that of placebo when given after cimoxatone. The plasma tyramine concentration required to induce a similar pressor effect averaged 130.5 ng ml-1 without pretreatment and 17.4 ng ml-1 after cimoxatone in the open study. Another plasma concentration, 16.4 ng ml-1, elicited a lower pressor effect in the double-blind study. The increased sensitivity to oral tyramine has two components: decreased presystemic clearance in the gut wall and increased sensitivity to circulating tyramine. The tyramine dose required to induce a pressor effect after cimoxatone is relatively higher than after irreversible inhibitors such as phenelzine. This may reflect the dose of cimoxatone used, the activity of monoamine oxidase form B (MAO-B) in the gut and liver or displacement of the predominantly reversible and predominantly competitive inhibitor, cimoxatone, from the enzyme by a high local tyramine concentration.

Absorption↗