Drugs online research references
rti.org
Gemfibrozil (GEM) is a clofibrate analog used to treat moderate to severe hypertriglyceridemias. In lab animals, GEM causes peroxisome proliferation, an effect that has been associated with hepatocarcinogenesis in rats. In humans, hepatobiliary disorders, but not carcinogenesis, have been associated with GEM therapy. In the present study [14C]GEM was administered orally to rats at a dose of 2000 mg/kg. At various time points, radioactivity in urine was analyzed by liquid scintillation spectrometry, high-pressure liquid chromatography, liquid chromatography/mass spectrometryn, gas chromatography/mass spectroscopy, and nuclear magnetic resonance. Nine metabolites of GEM were identified, some that have not been reported previously. Although the majority of metabolites were glucuronidated, some nonglucuronidated metabolites were identified in urine, including a diol metabolite (both ring methyls hydroxylated), and the product of its further metabolism, the acid-alcohol derivative (ortho ring methyl hydroxylated, meta ring methyl completely oxidized to the acid). Hydroxylation of the aromatic ring also was a common pathway for GEM metabolism, leading to the production of two phenolic metabolites, only one of which was detected in the urine in the nonconjugated or free form. Also of interest was the finding that both acyl and ether glucuronides were produced, including both glucuronide forms of the same metabolite (e. g., 1-O-GlcUA, 5'-COOH-GEM, and 5'-COO-GlcUA-GEM); the positions and functionality of the glucuronide conjugates were identified using base hydrolysis or glucuronidase treatment, in combination with liquid chromatography/MSn and nuclear magnetic resonance.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9884324&dopt=Abstract
J Pharmacol Exp Ther. 1999 Feb;288(2):414-20.
Hepatic disposition of the acyl glucuronide1-O-gemfibrozil-beta-D-glucuronide: effects of dibromosulfophthalein on membrane transport and aglycone formation.
Sabordo L, Sallustio BC, Evans AM, Nation RL.
Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Woodville, South Australia.
The liver plays an important role in the disposition of acyl glucuronides by determining their extent of formation, biliary excretion, and efflux into blood. Thus, both intrahepatic and extrahepatic exposure to these reactive polar conjugates depends on the efficiency of hepatic transport mechanisms, which may be shared with other nonbile acid organic anions. Using the isolated perfused rat liver preparation, the hepatic disposition of the acyl glucuronide, 1-O-gemfibrozil-beta-D-glucuronide, was examined in the presence of the organic anion dibromosulfophthalein (DBSP). Using a recirculating system, livers were perfused for 90 min with an erythrocyte-free perfusion medium containing 1% (w/v) albumin and 1-O-gemfibrozil-beta-D-glucuronide (3 microM) alone (n = 6) or with DBSP (200 microM, n = 7). The glucuronide was avidly taken up by the liver, excreted into bile, and hydrolyzed within the liver to its aglycone, gemfibrozil. DBSP significantly (P <.05) lowered the conjugate's mean hepatic clearance (8.98-5.17 ml/min), intrinsic clearance (44.0-17.7 ml/min), and fraction eliminated in bile (72. 8-48.7% of the dose), while increasing perfusate gemfibrozil concentrations (0.52-0.92 microM at 90 min). Furthermore, DBSP significantly (P <.05) lowered the ratio of intrahepatic to unbound perfusate concentrations of 1-O-gemfibrozil-beta-D-glucuronide (139. 0-35.0) and showed a trend to lower the ratio of bile to intrahepatic concentrations (111.3-76.2, P =.05). Thus, the study demonstrated that DBSP inhibited both the sinusoidal uptake and canalicular transport of 1-O-gemfibrozil-beta-D-glucuronide, suggesting that the hepatic membrane transport of acyl glucuronides is carrier mediated and shared with other organic anions.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9918540&dopt=Abstract
intmed2.med.kyushu-u.ac.jp
Lipid-lowering fibrate drugs are known to affect the synthesis of fatty acids, which may alter the prostacyclin synthesis in diabetic patients. Therefore, the serum levels of precursor fatty acids and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha) were determined in ten hyperlipidemic patients with Type 2 diabetes before and after administration of gemfibrozil (900 mg/day) for 3 months, in comparison with the results in seven non-diabetic hyperlipidemic patients. Gemfibrozil significantly reduced the serum concentration of dihomo-7-linolenic acid, total cholesterol and triglycerides, but did not affect the serum levels of arachidonic acid and 6-keto PGF1alpha in diabetic and non-diabetic patients. Thus, gemfibrozil did not affect the synthesis of prostacyclin in spite of the reduction of precursor fatty acids in diabetic and non-diabetic patients.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9925344&dopt=Abstract
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