The Effects of Pretreatment of Mice with Norethindrone on the Metabolism of 14C-imipramine by the Liver Microsomal Drug-Metabolizing Enzymes

1974 ◽  
Vol 52 (1) ◽  
pp. 28-38 ◽  
Author(s):  
G. D. Bellward ◽  
R. G. Morgan ◽  
V. H. Szombathy
Keyword(s):  
Female Mouse ◽  
Mouse Liver ◽  
Competitive Inhibition ◽  
Drug Metabolizing Enzymes ◽  
Concurrent Administration ◽  
Metabolizing Enzymes ◽  
Assay Procedure ◽  
Cytochrome P 450 ◽  
Enzyme Source

An assay procedure for the metabolism of 14C-imipramine in vitro is described. Using female mouse liver as the enzyme source, the conditions of the assay have been determined for the formation of 2-hydroxyimipramine, desmethylimipramine, and imipramine-N-oxide. Demethylation was linear up to a substrate concentration of 120 μg/3.5 ml, N-oxidation was linear up to a concentration of imipramine of 70 μg/3.5 ml, and hydroxylation up to 20 μg/3.5 ml of reaction mixture. Desmethylimipramine competitively inhibited both hydroxylation and demethylation, whereas imipramine-N-oxide had no effect. Pretreatment of mice with norethindrone decreased hydroxylation, and increased demethylation. Cytochrome P-450 was also increased by this progestin; N-oxidation was not changed. The effects of concurrent administration of norethindrone with known inducers or inhibitors of drug metabolism have been determined. From these experiments, it was concluded that the induction of cytochrome P-450 by norethindrone is not responsible for the increased demethylation of imipramine. Rather, it appeared that competitive inhibition of hydroxylation of imipramine by the norethindrone allowed more of the drug to be demethylated.

Effects of chronic ethanol administration in the rat: relative dependency on dietary lipids. II. Paradoxical role of linoleate in the induction of hepatic drug-metabolizing enzymes in vitro

1977 ◽  
Vol 55 (1) ◽  
pp. 34-41 ◽  
Author(s):  
Jean-Gil Joly ◽  
Claude Hétu
Keyword(s):  
Dietary Lipid ◽  
Dietary Lipids ◽  
Chronic Ethanol ◽  
Ethanol Administration ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Drug Biotransformation ◽  
Chronic Ethanol Administration ◽  
Cytochrome P 450

The effect of chronic ethanol administration on the hepatic microsomal cytochrome P-450 content and activities of NADPH – cytochrome P-450 reductase (EC 1.6.2.4), benzphetamine demethylase, aniline hydroxylase (EC 1.14.14.1), and of the microsomal ethanol-oxidizing system were studied in various dietary models. When ethanol was given with linoleate as the only source of dietary lipid, the ethanol induction of these parameters was greater with diets containing 2 or 5% of total calories as linoleate than with diets containing 10% of total calories as linoleate. By contrast, when ethanol was given with high fat (35% of total calories) diets, the ethanol induction of these same parameters was slightly greater when linoleate provided 10% of total calories than when it provided 3% of calories. The apparent effect of dietary linoleate on the induction, by ethanol, of microsomal drug-metabolizing enzymes is markedly different when linoleate is given as the only source of dietary lipid as opposed to when it is given with other dietary lipids. Thus, conclusions on the effect of ethanol on hepatic microsomal drug-biotransformation enzymes, drawn from studies with dietary models in which linoleate provides the only source of dietary lipid, cannot be extended to dietary models of more complex lipid composition. When given as the only source of lipid, 2% of total calories in linoleate appears optimal for basal activity and inductibility, by ethanol, of mixed-function oxidases.

Selective aromatase inhibition by pyridoglutethimide, an analogue of aminoglutethimide

1990 ◽  
Vol 122 (5) ◽  
pp. 592-598 ◽  
Author(s):  
Jo Kitawaki ◽  
Takara Yamamoto ◽  
Mamoru Urabe ◽  
Takaya Tamura ◽  
Shigeo Inoue ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Inhibitory Effect ◽  
Side Chain ◽  
Aromatase Activity ◽  
Inhibitory Effects ◽  
Metabolizing Enzymes ◽  
Chain Cleavage ◽  
Steroid Hydroxylases ◽  
Cytochrome P 450

Abstract. The inhibitory effects of pyridoglutethimide (3-ethyl-3-(4-pyridyl)piperidine-2,6-dione), an analogue of aminoglutethimide, on aromatase and other cytochrome P-450-dependent steroid-metabolizing enzymes were studied in vitro. Pyridoglutethimide and aminoglutethimide showed competitive inhibition of human placental aromatase activity with apparent Ki values of 1.7 and 0.7 μmol/l, respectively. Both pyridoglutethimide and aminoglutethimide inhibited the aromatase activity of uterine leiomyoma and cultured choriocarcinoma Enami cells as well as immunopurified human placental aromatase cytochrome P-450 by more than 90%, with IC50 values of 10–19 and 5–7 μmol/l, respectively. These results might suggest that the inhibitors interacted directly with the aromatase cytochrome P-450 of these tissues. Aminoglutethimide inhibited bovine adrenal cholesterol side-chain cleavage activity with an IC50 value of 40 μmol/l and inhibited 21-hydroxylase activity slightly, but did ot inhibit 17α-, 1 1β- and 18-hydroxylase at concentrations up to 100 μmol/l. On the other hand, pyridoglutethimide had no inhibitory effect on any of these enzymes at concentrations up to 50 μmol/l, although it inhibited 11β- and 18-hydroxylase slightly at 100 μmol/l. These results indicated that pyridoglutethimide was an aromatase inhibitor of a comparable potency to aminoglutethimide, but that it did not inhibit other steroid hydroxylases.

scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

Sign in / Sign up

Export Citation Format

Share Document