Structure and Gene Polymorphism Affect the Metabolism of Statins / 中国药学杂志

Statins are the main drugs for high cholesterol. The different chemical structures affect the metabolize way of statins. Different chemical structures of statins lead to differences in hydrophobicity and affect the degree of membrane transport and tissue affinity. The differences in hydrophobicity may influence the absorption of statins and the distribution in important organs. The metabolism of statins in vivo is mainly related to drug metabolizing enzymes. Gene polymorphism affects the activity and capacity of enzymes and may influence the lipid-lowering effect of statins. This paper reviews the transshipment and metabolic characteristics of statins. We summarize the gene polymorphism on the effect of drug metabolism and conduct the clinical prescription.

Association between ABCB1 C3435T Polymorphism and Statins Effectiveness Among Chinese Population: A Meta-Analysis / 中国药学杂志

OBJECTIVE: To evaluate the association between ABCB1 C3435T polymorphism and statins effectiveness among Chinese population. METHODS: Databases including PubMed, Web of Scien, Cochrance Library, CNKI, WanFang Data and VIP were searched to retrieve the relevant references from the start to August 2016. A quality assessment was performed using the Methodological Index for Non-Randomized Studies(MINORS)criteria. Meta-analysis, sensitivity analysis(RevMan 5.3)were all done. RESULTS: A total of 4 studies were included for final Meta-analysis, involving 630 participants. The efficacy was evaluated by the change in TC (total cholesterol), TG(triglyceride), HDL-C(high density lipoprotein-cholesterol), and LDL-C(low density lipoprotein-cholesterol) after statin treatment. The pooled MDs were assessed for the dominant genetic model (CT+TT vs.CC), recessive genetic model (TT vs. CC+CT) and homozygote comparison (TT vs. CC).Overall, there was no statistically significant association for the four genetic models of statins effectiveness. CONCLUSION: There is no association between ABCB1 C3435T polymorphism and statins effectiveness among Chinese population.

Potential statin-drug interactions: prevalence and clinical significance.

BACKGROUND: Statins are cholesterol-lowering drugs widely used for cardiovascular prevention. Although safe when used alone, in combination with other drugs the likelihood of adverse drug reactions increases significantly. The exposure of the Bulgarian population to coprescriptions leading to potential statin-drug interactions is currently unknown. OBJECTIVE: The aim of this study was to investigate the incidence of coprescriptions involving statins and to compare the exposure of outpatients and inpatients to potential statin-drug interactions. SETTING: A cardiology clinic of the teaching University hospital in Varna, Bulgaria. METHOD: This observational retrospective study examined the medical records of hospitalized patients prescribed a statin in combination with potentially interacting drugs. Patients who entered the hospital with a statin coprescription (considered outpatients) were compared with those coprescribed a statin at discharge from hospital (considered inpatients). Potentially interacting drugs included inhibitors and inducers of cytochrome P450 (CYP) enzymes and drugs of narrow safety margin (coumarin anticoagulants, digitalis). MAIN OUTCOME MEASURE: The proportion of patients exposed to statin coprescriptions with potentially interacting drugs at hospital admission and discharge. SECONDARY OUTCOME MEASURES: laboratory evidence supporting possible statin-drug interactions. RESULTS: Out of 1641 hospitalized patients examined, 572 were prescribed a statin, either at hospital admission or discharge. Simvastatin was most commonly prescribed and simvastatin-drug coprescription predominated, especially at discharge. The exposure to all potential statin-drug interactions was similar at hospital admission (26.1%) and discharge (24.4%), as was the exposure to statin combinations with CYP inhibitors, 6.4% and 4%, correspondingly. Overall, more coprescriptions were generated, than were eliminated by hospital physicians. Amiodarone was the CYP inhibitor most frequently coprescribed. Of all interacting drugs acenocoumarol was the most commonly found, the proportions of statin-acenocoumarol coprescriptions being roughly the same at hospital entry (11.5%) and discharge (12.4%). In 7 patients out of 69 exposed to the combination, INR was found to be higher than 3, indicating a risk of over-anticoagulation. CONCLUSIONS: Potential statin-drug interactions are common. Although they do not differ between outpatient and inpatient settings, new hazardous coprescriptions are more frequently generated in hospital. Caution is required when acenocoumarol is coprescribed with statins, especially simvastatin.

Chimeric cytochromes P450 engineered by domain swapping and random mutagenesis for producing human metabolites of drugs.

Human drug metabolites produced by cytochrome P450 enzymes are critical for safety testing and may themselves act as drugs or leads in the drug discovery and development process. Here, highly active chimeric fusion proteins (chimeras) were obtained by reductase domain swapping of mutants at key catalytic residues of the heme domain with that of a natural variant (CYP102A1.2) of P450 BM3 (CYP102A1.1) from Bacillus megaterium. Random mutagenesis at the heme domain of the chimera was also used to generate chimeric mutants that were more active and diverse than the chimeras themselves. To determine whether the chimeras and several mutants of the highly active chimera displayed enhanced catalytic activity and, more importantly, whether they acquired activities of biotechnological importance, we measured the oxidation activities of the chimeras and chimeric mutants toward human P450 substrates, mainly drugs. Some of the chimeric mutants showed high activity toward typical human P450 substrates including drugs. Statin leads, especially chiral products, with inhibitory effects toward HMG-CoA reductase could be obtained from metabolites of statin drugs generated using these chimeric mutants. This study reveals the critical role of the reductase domain for the activity of P450 BM3 and shows that chimeras generated by domain swapping can be used to develop industrial enzymes for the synthesis of human metabolites from drugs and drug leads.

A prospective study of statin drug use and lower urinary tract symptoms in older men.

Dyslipidemia and chronic inflammation may play a role in the cause of lower urinary tract symptoms (LUTS) in older men. Use of statin drugs, which are prescribed to lower cholesterol and appear to reduce inflammation, may decrease the incidence or progression of LUTS. The associations of statin drug use with LUTS incidence and progression were prospectively evaluated in the Health Professionals Follow-up Study from 1992 to 2008. Hazard ratios and 95% confidence intervals of incident LUTS (from no or a low International Prostate Symptom Score (IPSS) of 0-7 to a moderate or worse IPSS of ≥15; n = 5,790 cases in 24,715 men) and of LUTS progression (from modest IPSS of 8-14 to severe IPSS of ≥20; n = 2,238 cases in 8,709 men) were calculated comparing current statin use with nonuse. The hazard ratios of LUTS incidence and progression comparing current use to nonuse were greater than 1. However, when comparisons were restricted to participants who used drugs to treat hypertension (a surrogate for uptake of medical care), statin use was not associated with LUTS incidence (hazard ratio = 1.02, 95% confidence interval: 0.94, 1.12) or progression (hazard ratio = 0.98, 95% confidence interval: 0.85, 1.13). Thus, statin use is unlikely to beneficially influence the development or course of LUTS. The present study highlights a methodological issue (confounding) that must be addressed in observational studies on the use of common drugs for indications other than the primary use.