Cancer ChemotherPharmacol (1994) 34:377-384 ~ ancer hemotherapyand narmacology 9 Springer-Verlag 1994 Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-effiux blocker K. S. Sridhar, A. Krishan, T. S. A. Samy, R. C. Duncan, A. Sauerteig, G. V. McPhee, M. E. Auguste, P. W. Benedetto Division of ExperimentalTherapeutics,Departments of Medicine and Radiation Oncology,Universityof Miami Medical School, Miami, FL 33136, USA Received: 8 September 1993/Accepted: 11 March 1994 Abstract. In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-rain i.v. infusion was 75 mg/m 2. The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ le- vels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m2 DOX as an i. v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/ m 2 PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m 2. Large interpatient variation in peak PCZ plasma levels (91-3215 ng/ml) was seen, with the plasma half-life (tV2c0 being approximately 57 min in patients given 135-180 mg! m 2 PCZ. The volume of distribution (Vd), total clearance (C1T), and area under the curve (AUC) were 350.1 + 183.8 1/m 2, 260.7___142.7 1 m 2 hq and 1539-/-922 ng ml h -I, respectively, in patients given 180 mg/m 2 PCZ and the respective values for patients receiving 135 mg/m 2 were 48.9+23.76 Urn2, 33.2_+2.62 1 m 2 h -I, and 4117+302 ng ml h-1. High PCZ plasma levels (> 600 ng/ml) were sus- tained in all patients treated with 135 mg/m 2 PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m 2 PCZ, and a > 10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19-22, 1993 Correspondence to: A. Krishan, Michigan Cancer Foundation, 110 East Warren Avenue, Detroit, MI 48201, USA patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m 2 with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase H trials. Key words: Drug effiux - Doxorubicin - Multiple drug resistance - Modulation - Prochlorperazine Introduction Rapid drug efflux may be a major mechanism for tumor cell resistance to a variety of natural products used in cancer chemotherapy [8, 11, 27]. The presence of the multiple drug resistance (MDR) gene and the gene product (170-kDa P-glycoprotein), which presumably acts as the putative efflux pump, has been described in a variety of normal and malignant cells [2, 4, 6, 12, 23]. It has been reasoned that if rapid drug efflux is the major mechanism by which resistant cells reduce cellular retention of a cy- totoxic agent, then blocking of this efflux by noncytotoxic drugs may enhance chemosensitivity. Several unrelated drugs such as verapamil (VPL), cyclosporine, quinidine, thaliblastine, tamoxifen, and phenothiazines have been used in vitro and in vivo to block drug efflux [1, 5, 7, 10, 14, 17-20, 25, 28, 37]. Earlier studies have shown that phenothiazines such as chlorpromazine (CPZ) and trifluoperazine (TFP) are potent blockers of doxorubicin (DOX) effiux [10, 14-16]. We have extensively studied and reported on the efflux- blocking activity of the phenothiazines CPZ, TFR and prochlorperazine (PCZ) in DOX-resistant P388 cells and in a variety of human tumor cells obtained from ascites and pleural fluid or after enzymatic disaggregation of solid tumor biopsies [14-16]. Coincubation of tumor cells with 1 gM (318 ng/ml) CPZ or PCZ (a noncytotoxic dose by