Pharmacokinetics And Relative Studides Of Intravaginal Administration Of Clindamycin Phosphate Ovule In Chinese Female Volunteers

Objective To estabilish an accurate and sensitive HPLC-MS method for thedetermination of Clindamycin in human serum;To investigate the pharmacokinetics of clindamycin phosphate ovule in healthy Chinese female volunteers after a single dose and multiple doses of 5.0g Clindamycin Phosphate Ovule;To study the relative bioavailability of ovule preparations of clindamycin phosphate and oral tablets of clidamycin hydrochloride;To evaluate the safety and tolerence of clindamycin phosphate ovule.Methods Mosapride was used as internal standard, After adding mosapride,the serum samples were alkalized with 0.1moL·L^-1 sodium hydroxide solution and extracted with acetic ether and were analysed by HPLC-MS method. The seperation was carried on a Hypersil ODS2 column (5μm,ID 4.0 × 200mm) at 25℃. The mobile phase was acetonitrile-5mmoL·L^-1 ammonium acetate solution (55:45), running at a flow rate of 0.8ml·min^-1.HPLC-MS method was performed with positive ion SIM mode detection of Clindamycin ([MH]⁺,m/z=425) and mosapride ([MH]⁺,m/z=422) as internal standard. Ten healthy Chinese female volunteers were vaginally given with 5.0g of clindamycin phosphate ovule (equivalent to 100mg clindamycin) once a dayfor single dose treatment, and 5.0g, once a day for 3 days, for multiple doses treatment. After a month of experiment of clindamycin phosphate ovule,ten healthy Chinese female volunteers were orally given 150mg clidamycin hydrochloride tablets for single dose treatmentBlood samples were collected at predetermined time-points and serum was removed and stored at -20 °C for analysis.The pharmacokinetic parameters of clidamycin were caculated. and evaluated by DAS software.Results1. The detection limit of Clindamycin in serum was O.Sngml"1, with a good linearilty in the range of 0.5³20ngmr1(r=0.9998). The average recovery was above 88%.2. The main pharmacokinetic parameters of clindamycin for single dose after intravaginal applications were as follow: tj/2 was (15.30+2.62) h, Tmax was (4.88 + 0.94) h, Cmax was (38.30+22.77) ng-ml"1, AUC0⁴8 was (686.62±316.73) ngml"!h, AUCo— was (783.45+351.19) ng-ml"1 h.3. The main pharmacokinetic parameters of clindamycin for multiple doses after intravaginal applications were as follow: Ua was (14.78+2.49) h, Tmax was (4.69+ 0.37) h, Cmax was (44.87+26.71) ng-ml"1, AUC0⁴8 was (921.65±436.12) ng-ml"1-h, AUC0 was(1015.68+456.95)ngml'h.4. The main pharmacokinetic parameters of clindamycin for single dose after oral applications of 150mg clindamycin hydrochloride tablets were as follow: tia was(3.6410.78)11,^ was (1.00±0.333)h, Cmax was (1334.13 + 535.91) ng-ml'1, AUC0²4was (3357.70+1013.15) ngmr'-h, AUC0^- was (3393.33 + 1037.40) ng-ml-'-h, Ke was (0.197+0.04) h'1.5. Systemic side effects and topical stimulation are not expected to occur with clindamycin phosphate vaginal ovule following intravaginal administration of clindamycin phosphate vaginal ovule in healthy female volunteers.Conclusions1. The assay was proved to be sensitive , accurate and convenient, and it is suitable for pharmacokinetic study of clindamycin after intravaginal administration ofclindamycin phosphate vaginal ovule and oral administration of clidamycin hydrochloride tablets in healthy female volunteers.2. The Cmax of clindamycin after a single dose and multiple doses of intravaginal administration of clindamycin phosphate ovule were obviously lower than that of oral preparations, which suggests that clindamycin phosphate ovule be absorbed slowly with systemic actions and be helpful to increase the topical concentration of clindamycin.3. The half-life time of clindamycin after a single dose and multiple doses of intravaginal administration of clindamycin phosphate ovule was about 15h, the mean retention time (MRT) was about 25 h, they were obviously longer than that of oral preparations , which suggests that clindamycin phosphate ovule be absorbed and eliminated slowly and the retention time of clindamycin phosphate ovule in body be prolonged , so it is suitable and safety foi once a day administration modle of clindamycin phosphate ovule in the evening.4 The relative bioavailability of clindamycin phosphate ovule after a single dose was about 29%.