scholarly journals Assessing CYP2C8-Mediated Pharmaceutical Excipient-Drug Interaction Potential: A Case Study of Tween 80 and Cremophor EL−35

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1492
Author(s):  
Chengming Wen ◽  
Haoyang Hu ◽  
Wenwen Zhang ◽  
Xin Liu ◽  
Xuehua Jiang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Interaction Potential ◽  
Liver Microsomes ◽  
Tween 80 ◽  
Drug Formulation ◽  
Rat Liver Microsomes ◽  
Hepatic Expression ◽  
Multiple Doses ◽  
Short Term Exposure

Pharmaceutical excipients (PEs) are substances included in drug formulations. Recent studies have revealed that some PEs can affect the activity of metabolic enzymes and drug transporters; however, the effects of PEs on CYP2C8 and its interaction potential with drugs remain unclear. In this study, we evaluated the effects of Tween 80 and EL−35 on CYP2C8 in vitro and further investigated their impacts on the PK of paclitaxel (PTX) in rats after single or multiple doses. The in vitro study indicated that Tween 80 and EL−35 inhibited CYP2C8 activity in human and rat liver microsomes. EL−35 also decreased the expression of CYP2C8 in HepG2 cells. In the in vivo study, Tween 80 did not alter the PK of PTX after single or multiple doses, whereas EL−35 administered for 14 days significantly increased the AUC and MRT of PTX. Further analysis indicated that multiple-dose EL−35 reduced the expression of Cyp2c22 and production of 6-OH-PTX in the rat liver. Our study suggested that short-term exposure to both PEs did not affect the PK of PTX in rats, but multiple doses of EL−35 increased the AUC and MRT of PTX by downregulating the hepatic expression of Cyp2c22. Such effects should be taken into consideration during drug formulation and administration.

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

2014 ◽  
Vol 92 (11) ◽  
pp. 961-964 ◽  
Author(s):  
Li Wang ◽  
Zhe Wang ◽  
Meng-ming Xia ◽  
Ying-ying Wang ◽  
Hai-yun Wang ◽  
...  
Keyword(s):  
Single Dose ◽  
Rat Liver ◽  
Liver Microsome ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Rat Liver Microsomes ◽  
Multiple Doses

The objective of this work was to investigate the effect of orally administered silybin on the pharmacokinetics of imatinib in rats and the metabolism of imatinib in human liver microsome and rat liver microsomes. Eighteen healthy male SD rats were randomly divided into 3 groups: group A (control group), group B (received multiple doses of 50 mg·kg−1 silybin for 15 consecutive days), and group C (received a single dose of 50 mg·kg−1 silybin). A single dose of imatinib was administered orally 30 min after administration of silybin (50 mg·kg−1). Imatinib plasma levels were measured by UPLC-MS/MS, and pharmacokinetic parameters were calculated by DAS 3.0 software (Bontz Inc., Beijing, China). In addition, human and rat liver microsome were performed to determine the effects of silybin metabolism of imatinib in vitro. The multiple doses or single dose of 50 mg·kg−1 silybin significantly decreased the area under the curve (0-t) of imatinib (p < 0.01). And the half-life (t1/2) of imatinib is significantly increased (p < 0.05 and p < 0.01, respectively). Also, silybin showed inhibitory effect on human and rat microsomes, the IC50 of silybin were 26.42 μmol·L−1 and 49.12 μmol·L−1 in human and rat liver microsomes, respectively. These results indicate that more attention should be paid to when imatinib is administrated combined with silybin.

In vitro metabolism in Sprague–Dawley rat liver microsomes of forsythoside A in different compositions of Shuang–Huang–Lian

Fitoterapia ◽  
2011 ◽  
Vol 82 (8) ◽  
pp. 1222-1230 ◽  
Author(s):  
Wei Zhou ◽  
Liu-qing Di ◽  
Jin-jun Shan ◽  
Xiao-lin Bi ◽  
Le-tian Chen ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Metabolism ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Sprague Dawley Rat

scholarly journals In Vitro Characterization of Borneol Metabolites by GC--MS Upon Incubation with Rat Liver Microsomes

2008 ◽  
Vol 46 (5) ◽  
pp. 419-423 ◽  
Author(s):  
R. Zhang ◽  
C.-h. Liu ◽  
T.-l. Huang ◽  
N.-s. Wang ◽  
S.-q. Mi
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
In Vitro Characterization

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

In vitro metabolism of T-2 toxin by rat liver microsomes

1986 ◽  
Vol 34 (5) ◽  
pp. 865-868 ◽  
Author(s):  
Catherine A. Knupp ◽  
Steven P. Swanson ◽  
William B. Buck
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Metabolism ◽  
Rat Liver Microsomes

THE ROLE OF THE ADRENAL GLAND IN THE CONTROL OF AMINO ACID INCORPORATION INTO PROTEIN OF ISOLATED RAT LIVER MICROSOMES

1960 ◽  
Vol 21 (2) ◽  
pp. 177-189 ◽  
Author(s):  
A. KORNER
Keyword(s):  
Amino Acid ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Female Rats ◽  
Male Rats ◽  
Rat Liver Microsomes ◽  
Hypophysectomized Rats ◽  
Normal Rat ◽  
Secondary Result

SUMMARY 1. Microsomes, isolated from rat liver a day after adrenalectomy, incorporate more radioactive amino acid into their protein in vitro than microsomes from normal rat liver. This enhanced rate of incorporation progressively declines with time after adrenalectomy until it reaches a plateau level which is below the normal rate of incorporation. 2. Following adrenalectomy microsomes isolated from liver of male rats show a greater rise in incorporating ability than those from liver of female rats, and maintain it longer. 3. Most of the increased incorporation observed in the in vitro system soon after adrenalectomy of the rat, and most of the decreased incorporation observed in rats adrenalectomized for some time, results from alterations in the microsomes which change their ability to incorporate activated amino acids into proteins. 4. Treatment of rats with cortisol acetate results in an increase in the ability of liver microsomes to incorporate amino acid into protein. This heightened incorporating ability is probably a secondary result of the breakdown of extrahepatic tissue protein which is stimulated by cortisol. 5. Somewhat similar responses to acute adrenalectomy and to treatment with cortisol were found in hypophysectomized rats. 6. The protein anabolic response of adrenalectomized rats to treatment with insulin, and of adrenalectomized-hypophysectomized rats to treatment with insulin or growth hormone, is greater than that shown by rats which possess adrenal glands.

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