scholarly journals Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies

2021 ◽  
Vol 14 (8) ◽  
pp. 719
Author(s):  
Jiawang Liu ◽  
Nirmal Rajasekaran ◽  
Ahamed Hossain ◽  
Changde Zhang ◽  
Shanchun Guo ◽  
...  
Keyword(s):  
Boronic Acid ◽  
Oral Bioavailability ◽  
Drug Exposure ◽  
Liver Microsomes ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Studies ◽  
Dependent Manner ◽  
Mucosal Permeability ◽  
Time Curve ◽  
Concentration Dependent Manner

Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested. ZB716 was metabolized primarily by CYP2D6 and CYP3A. In human liver microsomes, ZB716 demonstrated relatively low inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (when testosterone was used as the substrate), and no inhibition of CYP2B6 and 3A4 (when midazolam was used as the substrate). In assays for enzyme activity, ZB716 induced CYP1A2, 2B6, and 3A4 in a concentration-dependent manner. Single-dose and repeated-dose pharmacokinetic studies in rats and dogs showed oral bioavailability, dose-proportional drug exposure, and drug accumulation as measured by maximum concentration and area under the concentration–time curve (AUC).

scholarly journals Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

2001 ◽  
Vol 45 (2) ◽  
pp. 382-392 ◽  
Author(s):  
Zeruesenay Desta ◽  
Nadia V. Soukhova ◽  
David A. Flockhart
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Cost Effective ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Specific Substrate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
The Mean

ABSTRACT Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its Km value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 μM INH (∼6.86 μg/ml), the activities of these isoforms decreased by ∼40%. INH did not show significant inhibition (<10% at 50 μM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (Ki values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The meanKi values (± standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 ± 6.2 and 13 ± 2.4 μM, respectively. INH showed potent noncompetitive inhibition of CYP3A (Ki = 51.8 ± 2.5 to 75.9 ± 7.8 μM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (Ki = 110 ± 33 μM) and a competitive inhibitor of CYP2D6 (Ki = 126 ± 23 μM), but the mean Ki values for the inhibition of CYP2C9 and CYP1A2 were above 500 μM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.

scholarly journals Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1129
Author(s):  
Trang Nguyen Kieu Doan ◽  
Dang-Khoa Vo ◽  
Hyojung Kim ◽  
Anusha Balla ◽  
Yunjong Lee ◽  
...  
Keyword(s):  
Active Form ◽  
Liver Microsomes ◽  
Pharmacokinetic Studies ◽  
Uridine Diphosphate ◽  
Time Curve ◽  
Dihydroxyvitamin D3 ◽  
Additional Information ◽  
Protein Expressions

The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)2D3 in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)2D3 on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)2D3. Consistently, the in vitro metabolic kinetics (Vmax and CLint) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)2D3 treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CLNR) of BUP were significantly reduced by 1,25(OH)2D3, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CLR) of HBUP. Additionally, the AUC, CL, and CLNR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)2D3 in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (Vss) and lower plasma protein binding in 1,25(OH)2D3-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)2D3.

scholarly journals Eravacycline Pharmacokinetics and Challenges in Defining Humanized ExposureIn Vivo

2016 ◽  
Vol 60 (8) ◽  
pp. 5072-5075 ◽  
Author(s):  
Abrar K. Thabit ◽  
Marguerite L. Monogue ◽  
David P. Nicolau
Keyword(s):  
Human Exposure ◽  
Drug Exposure ◽  
Pharmacokinetic Profile ◽  
Free Drug ◽  
Infection Model ◽  
Exposure Level ◽  
Time Curve ◽  
Unbound Fraction ◽  
Binding Profile ◽  
Concentration Time

ABSTRACTWe assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.

Evaluation of the effects of hydrophilic organic solvents on CYP3A-mediated drug-drug interaction in vitro

2006 ◽  
Vol 25 (12) ◽  
pp. 715-721 ◽  
Author(s):  
M Iwase ◽  
N Kurata ◽  
R Ehana ◽  
Y Nishimura ◽  
T Masamoto ◽  
...  
Keyword(s):  
Organic Solvent ◽  
Organic Solvents ◽  
Human Liver ◽  
Liver Microsomes ◽  
Dependent Manner ◽  
Cyp3a4 Activity ◽  
Modulation Effect ◽  
Concentration Dependent Manner ◽  
Hydroxylation Activity

This study evaluated the effects of the commonly used hydrophilic organic solvents, acetonitrile, methanol, ethanol, 1-propanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, polyethylene glycol and propylene glycol, on CYP3A in pooled human liver microsomes, using testosterone and midazolam as substrates. Furthermore, we examined the modulation effect of organic solvents on CYP3A inhibition by ketoconazole. Testosterone 6b-hydroxylation activity was potently inhibited in the presence of DMSO and 1-propanol in a concentration-dependent manner. Midazolam 1'-hydroxylation activity, however, was weakly inhibited only by 1% of DMSO, the highest concentration used in this study. Moreover, the potency of ketoconazole to inhibit CYP3A activities was variable, depending on the organic solvent used as a dissolving solvent for ketoconazole. Our data indicate that each organic solvent had an effect on CYP3A4 activity, evaluated by both substrates with different magnitudes. Furthermore, it was shown that the effects of organic solvents on CYP3A activity are substrate-dependent. The present study also shows that methanol had little effect on either substrate.

A study of the in vitro clinical interaction between lidocaine and premedications using rat liver microsomes

2002 ◽  
Vol 21 (8) ◽  
pp. 453-456 ◽  
Author(s):  
A Nagashima ◽  
E Tanaka ◽  
S Inomata ◽  
S Misawa
Keyword(s):  
Liver Microsomes ◽  
Competitive Inhibitor ◽  
Rat Liver Microsomes ◽  
Dependent Manner ◽  
Potential Importance ◽  
Concentration Dependent Manner ◽  
Hepatic Microsomes ◽  
The Relationship ◽  
Substrate Concentrations

In this study, we have investigated the relationship between lidocaine metabolism and premedication, i.e., psychotropic and anti-anxiety agents (diazepam, midazolam), hypnotics (pentobarbital, thiamylal), depolarizing muscular relaxants (vecuronium, pancuronium and suxamethonium), an active anti-hypertensive (clonidine) and an H2 receptor antagonist (cimetidine) using rat hepatic microsomes in vitro. Lidocaine metabolism was noncompetitively inhibited by midazolam (Ki=29.0 mM). Thilamylal was a moderate competitive inhibitor of lidocaine metabolism (Ki=77.8 mM). Pentobarbital, diazepam and cimetidine weakly inhibited lidocaine metabolism formation in a concentration-dependent manner at high substrate concentrations. On the other hand, vecuronium, pancuronium, suxamethonium and clonidine did not inhibit lidocaine metabolism over the therapeutic range. These results show that the interaction between lidocaine and midazolam and thiamylal, catalyzed by a similar cytochrome P450, is of potential importance in toxicological and clinical studies.

Inhibitory Effects of Garcinia cambogia Extract on CYP2B6 Enzyme Activity

Planta Medica ◽  
2017 ◽  
Vol 83 (11) ◽  
pp. 895-900 ◽  
Author(s):  
Jun Yu ◽  
Min Choi ◽  
Jong Park ◽  
Shaheed Rehman ◽  
Katsunori Nakamura ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Enzyme Activities ◽  
Liver Microsomes ◽  
Cytochrome P450 Enzyme ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Garcinia Cambogia ◽  
P450 Enzyme

AbstractThis study assessed the inhibitory effects of Garcinia cambogia extract on the cytochrome P450 enzymes in vitro. G. cambogia extract was incubated with cytochrome P450 isozyme-specific substrates in human liver microsomes and recombinant CYP2B6 isozyme, and the formation of the marker metabolites was measured to investigate the inhibitory potential on cytochrome P450 enzyme activities. The results showed that G. cambogia extract has significant inhibitory effects on CYP2B6 activity in a concentration-dependent manner. Furthermore, the inhibition was potentiated following preincubation with NADPH, indicating that G. cambogia extract is a time-dependent inhibitor of CYP2B6. Meanwhile, hydroxycitric acid, the major bioactive ingredient of G. cambogia extract, did not exhibit significant inhibition effects on cytochrome P450 enzyme activities. G. cambogia extract could modulate the pharmacokinetics of CYP2B6 substrate drugs and lead to interactions with those drugs. Therefore, caution may be required with respect to concomitant intake of dietary supplements containing G. cambogia extract with CYP2B6 substrates.

scholarly journals Relationship between Didanosine Exposure and Surrogate Marker Response in Human Immunodeficiency Virus-Infected Outpatients

1998 ◽  
Vol 42 (4) ◽  
pp. 821-826 ◽  
Author(s):  
John M. Adams ◽  
Mark J. Shelton ◽  
Ross G. Hewitt ◽  
Thaddeus H. Grasela ◽  
Mary DeRemer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Exposure ◽  
Surrogate Marker ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Cd4 Cell Count ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Cd4 Cell

ABSTRACT We used information available from routine clinic visits to characterize the pharmacokinetics of didanosine in 82 human immunodeficiency virus-infected patients. A total of 271 blood samples were collected for the measurement of didanosine concentrations in plasma (mean ± standard deviation [SD], 3.30 ± 2.21 samples/patient). Bayesian estimates of didanosine oral clearance (CLoral) were obtained for these patients by the POSTHOC option within the NONMEM software package. Population priors from a previous NONMEM analysis of didanosine pharmacokinetics were used. The mean ± SD CLoral was 132 ± 27.7 liters/h, which agrees reasonably well with estimates obtained from previous pharmacokinetic studies of didanosine. Estimates of individual didanosine exposure were then used to consider potential relationships between drug exposure and surrogate marker response over a 6-month period. No correlations were found between the didanosine area under the concentration-time curve from 0 to 6 months and the absolute CD4 cell count (r = 0.305; 0.1 <P < 0.2), weight response (r = 0.0857; P > 0.4), or percentage of CD4 lymphocytes (r = 0.0559; P > 0.4). Future efforts to characterize didanosine exposure in outpatients by random sampling methods should involve more directed efforts to limit residual variability in the data.

scholarly journals Pharmacokinetics, Safety, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor for Hepatitis C Virus, following Single Ascending Doses in Healthy Subjects

2012 ◽  
Vol 57 (3) ◽  
pp. 1201-1208 ◽  
Author(s):  
Jill Denning ◽  
Melanie Cornpropst ◽  
Stephen D. Flach ◽  
Michelle M. Berrey ◽  
William T. Symonds
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Maximum Concentration ◽  
Healthy Subjects ◽  
Drug Exposure ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Double Blind ◽  
Time Curve ◽  
Nucleotide Analog

ABSTRACTTo investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (tmax) values of 1.0 to 1.8 h, 1.5 to 3.0 h, and 3.0 to 6.0 h, respectively. The majority of systemic drug exposure was from the nucleoside GS-331007, with maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve to the last measurable concentration (AUC0–t) values at least 7- and 41-fold higher, respectively, than those obtained for GS-9851 after adjusting for differences in molecular weight. The terminal elimination half-life (t1/2) of GS-331007 increased with the dose, achieving at1/2of 25.7 h at 800 mg GS-9851. Dose proportionality was not observed for GS-331007. The majority of drug recovered in urine was in the form of GS-331007, with the percentage of this metabolite in urine samples ranging from 57% to 27% with increasing dose. GS-9851 was generally well tolerated, with no maximum tolerated dose identified. In conclusion, GS-9851 and its metabolites demonstrated a favorable pharmacokinetic profile consistent with once-daily dosing, and therefore, further clinical studies evaluating GS-9851 in HCV-infected patients are warranted.

scholarly journals Inhibitory Effects of Baicalin on the Expression and Activity of CYP3A Induce the Pharmacokinetic Changes of Midazolam in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Xin Tian ◽  
Zhen-Yu Cheng ◽  
Han Jin ◽  
Jie Gao ◽  
Hai-Ling Qiao
Keyword(s):  
Liver Microsomes ◽  
Flavonoid Compound ◽  
Rat Liver Microsomes ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Dose Dependent Decrease ◽  
Induced Changes ◽  
Regulatory Properties ◽  
Dose Dependent

Baicalin, a flavonoid compound isolated fromScutellaria baicalensis, has been shown to possess antiinflammatory, antiviral, antitumour, and immune regulatory properties. The present study evaluated the potential herb-drug interaction between baicalin and midazolam in rats. Coadministration of a single dose of baicalin (0.225, 0.45, and 0.90 g/kg, i.v.) with midazolam (10 mg/kg, i.v.) in rats resulted in a dose-dependent decrease in clearance (CL) from 25%  (P<0.05)to 34%  (P<0.001)with an increase inAUC0−∞from 47%  (P<0.05)to 53%  (P<0.01). Pretreatment of baicalin (0.90 g/kg, i.v., once daily for 7 days) also reduced midazolam CL by 43%  (P<0.001), with an increase inAUC0−∞by 87%  (P<0.01). Multiple doses of baicalin decreased the expression of hepatic CYP3A2 by approximately 58%  (P<0.01)and reduced midazolam 1′-hydroxylation by 23%  (P<0.001)and 4′-hydroxylation by 21%  (P<0.01)in the liver. In addition, baicalin competitively inhibited midazolam metabolism in rat liver microsomes in a concentration-dependent manner. Our data demonstrated that baicalin induced changes in the pharmacokinetics of midazolam in rats, which might be due to its inhibition of the hydroxylation activity and expression of CYP3A in the liver.

scholarly journals Scutellarin is Highly Likely to be Responsible for Drug-Drug Interactions Mediated by Hepatic Organic Anion-Transporting Polypeptide1B3

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Jianming Liu ◽  
Yongmei Guo ◽  
Yanqi Xu ◽  
Li Yuan ◽  
Huiting Zhu
Keyword(s):  
Drug Interactions ◽  
Peak Plasma ◽  
Organic Anion ◽  
Inhibitory Effect ◽  
Cerebrovascular Diseases ◽  
Dependent Manner ◽  
Time Curve ◽  
Concentration Dependent Manner ◽  
Apparent Clearance

Abstract Purpose Scutellarin, a flavonoid derived from the plant Erigeron breviscapus, is currently widely used to treat cerebrovascular diseases, liver-related diseases, and hyperlipidemia in china and other East Asian countries. This study was to investigate the effect of scutellarin on the uptake of rosuvastatin in HEK293T cells expressing human organic anion transporting polypeptide 1B3 (hOATP1B3) and rat OATP1B2 (rOATP1B2), respectively, and the effect of scutellarin on the pharmacokinetics of rosuvastatin in rats. Methods The newly established HEK293T cells expressing hOATP1B3 and rOATP1B2 were used to examine the effects of scutellarin and positive controls on in vitro rosuvastatin transport. After co-feeding with scutellarin, the rosuvastatin area under the plasma concentration-time curve (AUC0–24h), the peak plasma drug concentration (Cmax), elimination half-life (t1/2), time to reach Cmax (tmax), clearance (CL) and apparent clearance (CL/F) of rosuvastatin were determined in rats. Results Scutellarin inhibited hOATP1B3- and rOATP1B2-mediated rosuvastatin uptake (IC50: 45.54 ± 6.67 μM and 27.58 ± 3.97 μM) in vitro in a concentration-dependent manner. After co-feeding with scutellarin, the AUC0–24h and Cmax of rosuvastatin in rats increased to 27.4% and 37.7%, respectively. The t1/2 and tmax of rosuvastatin showed no significant change. Moreover, scutellarin caused 29.2% and 28.1% decrease in the CL and CL/F of rosuvastatin. Conclusion Scutellarin may inhibit the hOATP1B3- and rOATP1B2-mediated transport of rosuvastatin in vitro, and exerts a moderate inhibitory effect on the pharmacokinetics of rosuvastatin in rats. Scutellarin is highly likely to participate in drug-drug interactions, as mediated by OATP1B3 in humans.

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