Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies.
Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies.
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丙氯拉嗪作为阿霉素外排阻滞剂：I 期临床和药代动力学研究。
DOI：
10.1007/bf00685030
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发表时间：
1993
影响因子：
3
通讯作者：
Benedetto,PW
中科院分区：
文献类型：
--
作者：
Sridhar,KS;Krishan,A;Samy,TS;Sauerteig,A;Wellham,LL;McPhee,G;Duncan,RC;Anac,SY;Ardalan,B;Benedetto,PW
Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m2PCZ followed by a standard dose of 60 mg/m2DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t1/2α (±SE), 20.9±5.3 min;t1/2β, 1.8±0.3 h; andt1/2γ, 21.9±5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254±886 l/m2, 60.2±13.5 l m−2h−1, and 1624±686 ng ml−1h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.
