Gemfibrozil

Gemfibrozil is an activator of PPAR-α, used as a lipid-lowering drug; Gemfibrozil is also a nonselective inhibitor of several P450 isoforms, with Ki values for CYP2C9, 2C19, 2C8, and 1A2 of 5.8, 24, 69, and 82 μM, respectively.

Signaling Pathways >> Metabolic Enzyme/Protease >> Cytochrome P450

Research Areas >> Cardiovascular Disease

Research Areas >> Metabolic Disease

PPAR-α

CYP2C9:5.8 μM (Ki)

CYP2C19:24 μM (Ki)

CYP2C8:69 μM (Ki)

CYP1A2:82 μM (Ki)

Gemfibrozil is an activator of PPAR-α, used as a lipid-lowering drug[1]; also a nonselective inhibitor of several P450 isoforms, with Ki values for CYP2C9, 2C19, 2C8, and 1A2 of 5.8, 24, 69, and 82 μM, respectively[3]. Gemfibrozil (100, 150, 200 μM) inhibits the cytokine-induced NO production in a concentration dependent manner in human U373MG astroglial cells, and such effects are not due to any change of the stability of iNOS mRNA. Gemfibrozil (50, 100, 200 μM) inhibits human iNOS promoter-derived luciferase activity in cytokine-stimulated human U373MG astroglial cells. Furthermore, Gemfibrozil (50, 100, 150, and 200 μM) shows no effects on the viability of the cells[1]. Gemfibrozil considerably inhibits both M-23 and M-1 formation (catalyzed by CYP2C8 and CYP3A4), with Ki (IC50) values of 69 μM (95 μM) and 273 μM (>250 μM), respectively, in human liver microsomes. Gemfibrozil (0-250 μM) dose dependently inhibits the formation of M-23 (IC50, 68 μM) and M-1 (IC50, 78 μM) in recombinant CYP2C8, but shows no appreciable effect on the formation of these metabolites in recombinant CYP3A4[3].

Gemfibrozil (62 mg/kg/day, p.o.) treatment initiated 3 days before spinal cord injury (SCI) causes decreased locomotor function, and induces a trend for decreased white matter sparing after injury in mice. Gemfibrozil (62 mg/kg/day, p.o.) decreases macrophage immunoreactivity but increases T cell infiltration into spared tissue[2].

Activities of CYP3A4 (testosterone 6β-hydroxylation) and CYP2C8 (paclitaxel 6α-hydroxylation) are determined. The marker substrate concentrations used, 25 μM testosterone and 1 to 5 μM paclitaxel, are comparable with or around the Km values of the reactions. Gemfibrozil is either coincubated at 37°C for 15 min with the marker substrate and NADPH (1 mM) before the reaction is initiated with human liver microsomes (0.1 mg/mL) or preincubated with human liver microsomes and NADPH for 15 min before adding the marker substrate[3].

Briefly, 400 μL of culture supernatant is allowed to react with 200 μL of Griess reagent and incubated at room temperature for 15 min. The optical density of the assay samples is measured spectrophotometrically at 570 nm. Fresh culture medium serves as the blank in all experiments. Nitrite concentrations are calculated from a standard curve derived from the reaction of NaNO2 in the assay[1].

Mice are given vehicle or gemfibrozil beginning 3 days before SCI to ensure drug availability at the time of the injury (n=5-6/group). The drug is delivered orally by dissolving it in ethanol (0.25% w/w of gemfibrozil) and coating food pellets such that each animal receives appr 62 mg/kg/day; chow for control groups is treated with ethanol. Ethanol for each group is allowed to completely evaporate before giving the food to the animals. In addition, animals receive an intraperitoneal injection of vehicle or gemfibrozil (500 µg dissolved in 200 µL PBS) 1 h after the injury, and then continued to receive the drug in their food until the end of the study (28 days post-injury)[2].

[1]. Pahan K, et al. Gemfibrozil, a lipid-lowering drug, inhibits the induction of nitric-oxide synthase in human astrocytes. J Biol Chem. 2002 Nov 29;277(48):45984-91. Epub 2002 Sep 18.

[2]. Almad A, et al. The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice. Exp Neurol. 2011 Dec;232(2):309-17.

[3]. Wang JS, et al. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos. 2002 Dec;30(12):1352-6.

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MOLECULAR FORMULA :

C15-H22-O3

MOLECULAR WEIGHT :

250.37

WISWESSER LINE NOTATION :

QVX1&1&3OR B1 E1

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

18 gm/kg/3Y-I

TOXIC EFFECTS :

Behavioral - muscle weakness Kidney, Ureter, Bladder - changes in tubules (including acute renal failure, acute tubular necrosis)

REFERENCE :

AIMDAP Archives of Internal Medicine. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1908- Volume(issue)/page/year: 151,1873,1991

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1414 mg/kg

TOXIC EFFECTS :

Behavioral - altered sleep time (including change in righting reflex) Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 25,645,1997

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

445 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity)

REFERENCE :

TOVEFN Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown Volume(issue)/page/year: (6),38,1995

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2218 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity)

REFERENCE :

TOVEFN Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown Volume(issue)/page/year: (6),38,1995

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

2 gm/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Gastrointestinal - nausea or vomiting Gastrointestinal - other changes

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 25,699,1997 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

2864 mg/kg/13D-C

TOXIC EFFECTS :

Liver - changes in liver weight

REFERENCE :

JJATDK JAT, Journal of Applied Toxicology. (John Wiley & Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- Volume(issue)/page/year: 17,47,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

13650 mg/kg/13W-C

TOXIC EFFECTS :

Liver - other changes Kidney, Ureter, Bladder - changes in bladder weight Blood - changes in bone marrow (not otherwise specified)

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 25,653,1997

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

27300 mg/kg/13-I

TOXIC EFFECTS :

Liver - changes in liver weight Blood - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 25,703,1997

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

54600 mg/kg/1Y-I

TOXIC EFFECTS :

Liver - other changes Blood - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 25,703,1997

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Bird - quail

DOSE/DURATION :

5600 mg/kg/4W-I

TOXIC EFFECTS :

Endocrine - other changes Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol)

REFERENCE :

IJEBA6 Indian Journal of Experimental Biology. (Publications & Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- Volume(issue)/page/year: 34,987,1996 ** TUMORIGENIC DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

218 gm/kg/2Y-C

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Liver - tumors Reproductive - Tumorigenic effects - testicular tumors

REFERENCE :

JJIND8 JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. Volume(issue)/page/year: 67,1105,1981

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

16 gm/kg/78W-C

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Liver - tumors

REFERENCE :

JJIND8 JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. Volume(issue)/page/year: 67,1105,1981

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

22 gm/kg/2Y-C

TOXIC EFFECTS :

Tumorigenic - neoplastic by RTECS criteria Endocrine - tumors Reproductive - Tumorigenic effects - testicular tumors

REFERENCE :

JJIND8 JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. Volume(issue)/page/year: 67,1105,1981 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

2648 mg/kg

SEX/DURATION :

female 15-22 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 8,454,1987

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

18910 mg/kg

SEX/DURATION :

male 61 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - male fertility index (e.g. # males impregnating females per # males exposed to fertile nonpregnant females)

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 8,454,1987 *** REVIEWS *** IARC Cancer Review:Animal Limited Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 66,427,1996 IARC Cancer Review:Human Inadequate Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 66,427,1996 IARC Cancer Review:Group 3 IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 66,427,1996