Metabolic syndrome (MetS) is a cluster of risk factors that increase the likelihood of developing cardiovascular, metabolic and other diseases. The pharmacological management of MetS often involves polypharmacy, making it essential to understand how drug-metabolising enzymes, transporters, transcription factors and other proteins involved are affected under different metabolic conditions. This study investigated the relative mRNA expression of key hepatic and intestinal genes involved in drug metabolism, including Cyp1a2, Cyp3a23, Cyp2d1, Cyp2c11, Cyp2c6, Cyp2e1, Cyp7a1, Cyp2b1, Cyp2a1, Abcg5, Abcg8, Abcb1, Nr1i3, Nr1i2, Ahr, Gsta1 and Comt, in four nonobese rat models of MetS: hereditary hypertriglyceridaemic (HHTg), spontaneously hypertensive rat (SHR), SHR expressing transgenic human C-reactive protein (SHR-CRP), and bilaterally ovariectomised Wistar (W-OVX), compared to Wistar controls. Gene expression was quantified by RT-PCR with data normalised using the ΔΔCt method. Between the models studied, measurements showed significant differences in the liver. The upregulation of Cyp2c6 and Cyp3a23 was observed only in SHR; upregulated Cyp2d1 was found in SHR as well as in HHTg rats. The downregulated Cyp1a2 was measured in a condition of hypertriglyceridemia, postmenopause or hypertension. These findings highlight model-specific alterations in gene expression that may affect drug metabolism and interactions. The HHTg may be, in particular, a suitable model for preclinical studies focusing on intestinal drug-drug interactions in MetS-related conditions.

• Keywords
• drug metabolism, metabolic syndrome, rat model,
• MeSH
• Liver metabolism   enzymology   MeSH
• Rats MeSH
• Humans MeSH
• Membrane Transport Proteins * genetics   metabolism   MeSH
• RNA, Messenger * metabolism   genetics   MeSH
• Metabolic Syndrome * genetics   metabolism   MeSH
• Disease Models, Animal MeSH
• Rats, Inbred SHR MeSH
• Rats, Wistar MeSH
• Receptors, Cytoplasmic and Nuclear * genetics   metabolism   MeSH
• Cytochrome P-450 Enzyme System * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Membrane Transport Proteins * MeSH
• RNA, Messenger * MeSH
• Receptors, Cytoplasmic and Nuclear * MeSH
• Cytochrome P-450 Enzyme System * MeSH

BACKGROUND: CYP2C9*3 allele has been reported to correlate with increased plasma concentration of fluvastatin active form in healthy volunteers. We analyzed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. MATERIAL/METHODS: The study was prospective, without any interventions to standard procedures of hypolipidemic treatment. CYP2C9 genotype was determined by PCR-RFLP assay in 87 patients on concomitant fluvastatin therapy, in 48 patients on monotherapy, and in a control group of 254 healthy volunteers of Czech nationality. Biochemical and clinical data were collected before the initiation of fluvastatin treatment and 12 weeks later. RESULTS: The frequency of CYP2C9 alleles did not differ significantly among groups of patients and volunteers. The most frequently observed allele was CYP2C9*2. Treatment with 80 mg of fluvastatin daily of 48 patients on monotherapy for 12 weeks resulted in mean low-density lipoprotein cholesterol (LDL-C) reduction by 25%, mean serum total cholesterol (TC) reduction by 21%, and mean triglyceride (TG) reduction by 28%. The CYP2C9*1/*3 genotype was associated with a decrease in LDL-C levels (by 40.0% for CYP2C9*1/*3, but only by 22.4% for CYP2C9*1/*1), and with the reduction of TC (by 28.6% in CYP2C9*1/*3 versus 20.2% in CYP2C9*1/*1). CONCLUSIONS: In hypercholesterolemic patients, LDL-C serum concentration was decreased more significantly in fluvastatin-treated subjects bearing the CYP2C9*1/*3 genotype compared to CYP2C9*1/*1 genotype. However, due to rare occurrence of some CYP genotypes, it was impossible to report a definitive positive genotype-fluvastatin effect association.

• MeSH
• Alleles MeSH
• Anticholesteremic Agents adverse effects   pharmacology   MeSH
• Aryl Hydrocarbon Hydroxylases genetics   MeSH
• Cholesterol blood   MeSH
• Cytochrome P-450 CYP2C9 MeSH
• Demography MeSH
• Adult MeSH
• Fluvastatin MeSH
• Gene Frequency genetics   MeSH
• Genotype MeSH
• Hypercholesterolemia blood   drug therapy   genetics   MeSH
• Indoles adverse effects   pharmacology   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Fatty Acids, Monounsaturated adverse effects   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prevalence MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czechoslovakia MeSH
• Names of Substances
• Anticholesteremic Agents MeSH
• Aryl Hydrocarbon Hydroxylases MeSH
• Cholesterol MeSH
• CYP2C9 protein, human MeSH Browser
• Cytochrome P-450 CYP2C9 MeSH
• Fluvastatin MeSH
• Indoles MeSH
• Fatty Acids, Monounsaturated MeSH

Methamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam's metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

• MeSH
• Alcohol Oxidoreductases physiology   MeSH
• Aryl Hydrocarbon Hydroxylases physiology   MeSH
• Cytochrome P-450 CYP3A MeSH
• Dextromethorphan pharmacokinetics   MeSH
• Rats MeSH
• Drug Interactions MeSH
• Methamphetamine pharmacology   MeSH
• Midazolam pharmacokinetics   MeSH
• Oxidoreductases, N-Demethylating physiology   MeSH
• Rats, Wistar MeSH
• Cytochrome P450 Family 2 MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alcohol Oxidoreductases MeSH
• Aryl Hydrocarbon Hydroxylases MeSH
• Cyp2d1 protein, rat MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• Dextromethorphan MeSH
• Methamphetamine MeSH
• Midazolam MeSH
• Oxidoreductases, N-Demethylating MeSH
• Cytochrome P450 Family 2 MeSH