Tamsulosin is a medication used to treat symptomatic benign prostatic hyperplasia (BPH) and chronic prostatitis, help with the passage of kidney stones, and for urinary retention along with other measures. Tamsulosin is a selective α1 receptor antagonist that has preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in the blood vessels. When alpha 1 receptors in the bladder neck and the prostate are blocked, this causes a relaxation in smooth muscle and therefore less resistance to urinary flow. Due to this, the pain associated with BPH can be reduced. Tamsulosin is metabolized by the liver enzymes CYP2D6 and CYP3A4. Tamsulosin is metabolized to M-3 and M-4 by CYP2D6 enzyme and to M-1 by CYP3A4 enzyme.
The CYP2D6 enzyme has more than 113 modified polymorphisms. Among them, CYP2D6 * 3, * 4, * 5, * 6 are defective alleles of CYP2D6 and have no enzyme activity. Among the Asian broad / intermediate metabolites, the three most common alleles of the CYP2D6 gene are CYP2D6 * 1, * 2, and * 10. The mutant allele of CYP2D6 (CYP2D6 * 2) does not affect enzyme activity, but the CYP2D6 * 10 allele causes low expression and affinity of CYP2D6. These show pharmacokinetic difference of tamsulosin in relation to the genotype of CYP2D6.
The physiologically based pharmacokinetics (PBPK) model is a useful tool for deriving internal dose assessments from exposure to chemicals through the integration of doses, the physiological structure of mammalian species, and the physicochemical properties of specific chemicals. This technology has demonstrated its potential in the context of toxicological risk assessment and drug research and development processes. In the present study, the PBPK model was used to predict tamsulosin pharmacokinetics in association with CYP2D6 genotypes. This model can be used to predict the individual treatment and efficacy of tamsulosin accoding to the CYP2D6 gene.
To create PBPK (physiologically based pharmacokinetics) modeling of tamsulosin, clinical trials of tamsulosin were conducted. A total of 823 volunteers had been genotyped for the CYP2D6 gene polymorphism and 40 subjects participated in the study. All the participants were healthy male Korean. 16 subjects with CYP2D6*1/*1 (Group 1) genotype, 12 subjects with CYP2D6*1/*10 (Group 2) and 12 subjects with CYP2D6*10/*10 genotype (Group 3). After overnight fasting, each subjects were administered 0.2 mg single oral dose of tamsulosin with 240 mL of water. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24,36 and 48 hr after drug administration of tamsulosin. The plasma concentrations of tamsulosin were measured using an HPLC system.
The metabolic pathway of tamsulosin is shown in Figure 1. The mean plasma concentration-time profiles for pharmacokinetic parameters of tamsulosin in the CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 groups are shown in Figure 2. Individual values for pharmacokinetic parameters of tamsulosin in the CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 groups are shown in Figure 3. As a result, reduced CYP2D6 enzyme activity leads to higher tamsulosin exposure.
The PBPK model was based on a plasma concentration-time profile of pharmacokinetic studies. PBPK modeling in observed data, all the pharmacokinetic parameters are within the maximum and minimum values, so a fairly appropriate simulation model was created. PBPK modeling in population data, the predicted value model validation and evaluation were performed within a two-fold error range (Simulated data / Observed data within 0.5 to 2). In validation with two-fold error, all pharmacokinetic parameters are within acceptable range.
PBPK models can be used to predict pharmacokinetic behavior in specific virtual individuals or groups using realistic physiological traits. The use of a predictive population model allows for a preliminary assessment of the physiological properties of drug pharmacokinetic behavior prior to clinical studies. Also, the proposed model generation data can lead to optimization of tamsulosin pharmacokinetics and therapy according to the CYP2D6 gene polymorphism and may be useful in improving the clinical study design required in the drug development process.
Won Ki Chae– Graduated School Student, Sungkyunkwan University, Suwon-si, Gyeonggi-do