Gene detection, precise prevention! CYP3A5 gene polymorphism and psychotropic drugs

The previous editor introduced the effect of CYP3A5 gene polymorphism on calcium channel blockers and immunosuppressants.

As an important drug metabolizing enzyme in the human cytochrome family, CYP3A5 enzyme participates in the metabolism of other drugs in addition to the above two types of drugs, such as:

Psychiatric drugs midazolam, alprazolam, risperidone, antibiotic drugs azithromycin, clarithromycin, adrenal corticosteroid drugs cortisone, etc.

Midazolam, which has hypnotic and sedative effects, is a psychotropic drug widely used in the first-line clinic.

Dr. Lawrence Soon-U Lee from National University of Singapore and his team selected 24 patients with advanced cancer in Asia to evaluate demographic data (age and weight, etc.), clinical blood diagnostic indicators (total bilirubin, serum albumin, etc.), and genetic polymorphisms The effect of different variables of sex (CYP3A5 genotype, CYP3A4 genotype) on the pharmacokinetics of midazolam.

Basic model, final model,

Self-service resampling pharmacokinetic evaluation

The subjects were given 1 mg midazolam intravenously on the day before taking the chemotherapy drugs, and blood samples were collected at different time periods after the medication, and the plasma midazolam and its main metabolite 1'-hydroxyl were analyzed by liquid chromatography/mass spectrometry The concentration of midazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG). Extract blood genomic DNA and analyze genotype.

There was no expression of CYP3A4; of the 24 subjects, 17 cases of CYP3A5 expression (6 cases of CYP3A5*1/*1 type, 11 cases of CYP3A5*1/*3 type), 7 cases of CYP3A5 expression (CYP3A5*3/ *3 type).

Subject characteristic data statistics

Model analysis results: CYP3A5*3 type and total bilirubin level significantly affect midazolam clearance (CLMDZ); assuming that the subjects are all at the median level of total bilirubin 11µmol/L, CLMDZ for CYP3A5 expression is 15L/ h, CLMDZ of CYP3A5 not expressing is 11L/h.

Body weight can significantly affect the clearance and distribution of 1OHM. If the weight of subjects is set to be a median of 55kg, the clearance and distribution of 1OHM are 138L/h and 90L, respectively.

In addition, the model data also showed that creatine liver clearance variables can significantly affect the clearance of the metabolite HMG.