The plasma concentration of gliclazide was eliminated by at least two phases, and the terminal half-life was long (>: 100 hour), which was related to the saturated combination of gliclazide and DPP-4. Long half-life will not cause drug accumulation. It has been proved that the effective half-life of gliclazide after oral administration of 5 mg is about 65438 02 hours. After daily administration of 1 time, the steady-state plasma concentration of 5mg of gliglitazone was reached after the third administration, and the Cmax and AUC at the steady state were increased by 1.3 times compared with the first administration. The self-variation coefficient and inter-variation coefficient of gliclazide AUC are small (12.6% and 28.5% respectively). In the dose range of 1 ~ 10 mg, the plasma AUC of gliclazide increased in a way lower than the dose ratio. The pharmacokinetics of gliclazide in healthy volunteers is usually similar to that in patients with type 2 diabetes.
absorb
The absolute bioavailability of gliclazide is about 30%. High-fat diet can reduce Cmax 15% and increase AUC 4%; This effect has no clinical relevance. Rosiglitazone can be taken with food or on an empty stomach.
Be distributed
After a single intravenous injection of 5 mg, the steady-state apparent distribution volume of healthy subjects is about11100L, which indicates that gliclazide is widely distributed in tissues. The plasma protein binding rate of gliclazide decreased from about 99% at 1 nmol/L to 75% at ≥30 nmol/L? This shows that the saturation of DPP-4 increases with the increase of liggliptin concentration. At the high concentration where DPP-4 is completely saturated, there is still 70%? 80% of the liggliptin is bound to plasma protein, so there is 30% in plasma? 20% of gliclazide is in an unbound state. The plasma binding rate of patients with renal insufficiency or hepatic insufficiency is not affected.
To metabolize.
After oral administration, most (about 90%) of the gliclazidine was excreted in prototype form, indicating that metabolism is a secondary elimination pathway. A small part of the absorbed gliclazide was metabolized into a metabolite with no pharmacological activity, and its steady-state exposure level was 13.3% of that of gliclazide.
secrete
After oral administration of [C] liggliptin to healthy subjects, about 85% of the radioactivity was eliminated by intestinal and liver system (80%) or urine (5%) within 4 days. At steady state, the renal clearance rate is about 70 ml/min.
Pharmacokinetics of special population
Renal insufficiency
An open pharmacokinetic study was conducted to evaluate the pharmacokinetics of 5 mg gliclazide in male and female patients with different degrees of chronic renal insufficiency. Six healthy subjects with normal renal function (creatinine clearance rate [CrCl]≥80 ml/min) and six patients with type 2 diabetes with mild renal insufficiency (CRCL: 50)
Under steady state, the exposure level of patients with mild renal insufficiency is equivalent to that of healthy subjects.
In patients with moderate renal insufficiency, the steady-state exposure of glitazone was higher than that of healthy subjects (AUCζ, ss increased by 765,438+0%, Cmax increased by 46%). The increase of exposure level is not accompanied by the extension of accumulation half-life, terminal half-life or accumulation coefficient. The renal excretion of gliclazide is less than 5% of the dose, which is not affected by the decline of renal function.
The steady-state exposure level of type 2 diabetic patients with severe renal insufficiency increased by about 40% compared with those with normal renal function (AUC ζ, ss increased by 42%, Cmax increased by 35%). For two groups of patients with type 2 diabetes, the renal excretion is less than 7% of the given dose.
The results of population pharmacokinetic analysis further support these findings.
hepatic insufficiency
In patients with mild liver dysfunction (Child-Pugh grade A), the steady-state exposure level (AUCζ, ss) of gliclazide is about 25% lower than that of healthy subjects, and the Cmax is about 36%. In patients with moderate liver dysfunction (Child-Pugh grade B), the AUCζ and ss of gliclazide were about 65,438 04% lower than those of healthy subjects, and the Cmax was about 8% lower. In patients with severe liver dysfunction (Child-Pugh C grade), the AUC ζ and SS of gliclazide are comparable to those of healthy subjects, while the Cmax is about 23% lower. In patients with hepatic insufficiency, the decrease of pharmacokinetic parameters did not lead to the decrease of inhibition.
Body mass index (BMI)/weight
There is no need to adjust the dose according to the body mass index/weight. According to the analysis of population pharmacokinetics, body mass index/weight has no clinical significance to the pharmacokinetics of gliclazide.
gender
There is no need to adjust the dose according to sex. According to the analysis of population pharmacokinetics, gender has no clinical effect on the pharmacokinetics of gliclazide.
the aged
According to the analysis of population pharmacokinetics, age has no clinical effect on the pharmacokinetics of gliclazide.
children
The pharmacokinetic characteristics of gliclazide in children have not been studied.
race
There is no need to adjust the dose according to race. According to the available pharmacokinetic data, race has no clinical effect on the pharmacokinetics of gliclazide, including white, Hispanic, black and Asian patients.