Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients.

WHAT IS KNOWN AND OBJECTIVE: The calcium channel blocker diltiazem has been used widely as a cyclosporine (CsA)/tacrolimus-sparing agent. However, considerable interpatient variability in diltiazem's CsA/tacrolimus-sparing effect has been observed in many clinical studies. This study was carried out to investigate the impacts of the CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients. METHODS: Two hundred and twenty-five Chinese renal transplant patients were genotyped for CYP3A4*1G and CYP3A5*3. The predose and post-dose plasma concentrations of diltiazem and its main metabolisms were determined by HPLC. The relationships between the genotypes and pharmacokinetics were investigated. RESULTS AND DISCUSSION: The dose-adjusted concentrations and pharmacokinetics of diltiazem and its main metabolites were significantly affected by CYP3A4 *1G and CYP3A5*3 alleles. Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted trough concentration and AUC of diltiazem and its main metabolites compared with those with CYP3A4*1G*1G(P<0·05). The dose-adjusted trough levels and AUC of diltiazem and its main metabolites were significantly lower in CYP3A5*1*1 carriers than in CYP3A5*3 carriers (P < 0·05). WHAT IS NEW AND CONCLUSION: The CYP3A4*1G and CYP3A5*3 genetic polymorphisms are closely related to the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.

CYP3A5 polymorphism, amlodipine and hypertension.

As a major cardiovascular risk factor for stroke, coronary artery disease, heart failure and end-stage renal disease, hypertension affects approximately one billion people and causes large economic burden worldwide. Cytochrome P450 3A5 (CYP3A5), belonging to the CYP3A subfamily, has been implicated in the regulation of blood pressure and may serve as a potential risk factor for the development of hypertension. Increased CYP3A5 activity could cause sodium and water retention by affecting the metabolism of cortisol in the kidneys. Furthermore, polymorphic CYP3A5 genotypes have been shown to cause differences in blood pressure response to antihypertensive drugs. Several studies have investigated the role of CYP3A5 in blood pressure response to amlodipine. However, recent data on the role of CYP3A5 in hypertension development and treatment are inconsistent. This review summarizes what is known regarding the relationship of CYP3A5 with hypertension, discusses the limitations in present studies, highlights the gaps and directs research to this field.

[Ripening effect of mylis and tiluoan on the uterine cervix in pregnant rats].

Effect of Mylis and Tiluoan on cervical ripening and blood levels of estradiol and progesterone of pregnant rats were studied. Dehydroepiandrosterone (DHA) is the main component in both of the drugs. Pregnant rats groups were given the drugs on the 19th day of gestation at dosage of 10, 20 and 40 mg/kg respectively. The results indicated that both drugs at different dose were able to significantly decrease the cervical extensibility, to dilate the cervical OS, increase the cervical wet weight, and elevate the blood estradiol level, lower the progesterone concentration. It indicated that DHA enhances estradiol synthesis and suppresses progesterone secretion.

[Effect of dihydroepiandrosterone sulfate on the tension of uterine cervix and its mechanisms].

After i.v. injection of dihydroepiandrosterone sulfate (DHA-S) at 20 or 40 mg/kg to female rats on day 19 of gestation, the tension and hydroxyproline level of uterine cervix were decreased obviously. However, DHA-S at 10 mg/kg showed no effect on the tension of uterine cervix. DHA-S in vitro, at 0.1 mg/kg significantly increased estradiol secretion in the ovaries and placenta of late pregnant rats.

[Effects of diphenoxylate hydrochloride and dl-15 methyl prostaglandin F2 alpha methyl ester on rat luteal cells].

Diphenoxylate hydrochloride (R1132) at concentrations of 10 and 20 micrograms/ml or dl-15 methyl-PGF2 alpha methyl ester (PG05) at levels of 5 and 10 micrograms/ml was shown to have no effect on progesterone secretion by luteal cells in vitro in the absence of hCG. A marked increase in progesterone level was elicited by hCG as high as 3-8 fold the original value. The steroidogenic response of luteal cells to hCG was inhibited by R1132 and PG05. R1132 at a daily dose of 10 mg/kg or PG05 at a daily dose of 0.1 mg/kg for 5 days showed no obvious effect on ovary progesterone secretion in pseudopregnant rat. However, treatment with R1132 10 mg/kg plus PG05 0.1 mg/kg resulted in a decrease in the progesterone production of ovary in vitro. R1132 and PG05 at doses of 50 mg/kg and 0.5 mg/kg, respectively, exhibited an inhibitory effect on the adenylate cyclase activity.