Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

Clinical pharmacology of N4-palmitoyl-1-β-d-arabinofuranosylcytosine in patients with hematologic malignancies

Summary The pharmacokinetics of oral N⁴-palmitoyl-1--d-arabinofuranosylcytosine (PLAC), a lipophilic and deaminase-resistant derivative of 1--d-arabinofuranosylcytosine (ara-C), were determined in patients with hematologic malignancies. The concentration of ara-C and 1--d-arabinofuranosyluracil (ara-U), metabolites of PLAC, were measured by radioimmunoassay and gas chromatography-mass spectrometry-mass fragmentography, respectively. The concentration of PLAC was determined by measuring ara-C, which was derived from PLAC by hydrolyzation. In six patients given an oral bolus of PLAC (300 mg/m²), the plasma-disappearance curve of PLAC corresponded to a one-compartment open model, including first-order absorption. The peak plasma level was 22.9±6.4 ng/ml, and the predicted time to reach the peak level was 2.5±1.0 h. The elimination half-life was 3.8±2.7 h. The plasma ara-C level increased slowly to 6.9 ng/ml during the 1st 2–3 h after administration and remained over 1.0 ng/ml for 12 h. Plasma ara-U was detectable for at least 24 h, with a peak concentration of 376 ng/ml at 6 h. Urinary PLAC excretion was below the limit of detection (5 ng/ml) in all cases. Prolonged urinary ara-C and ara-U excretion was detected, but the total recovery rate was low (6.7% in 24 h) and varied between patients. In spite of the lipophilic nature of the drug, the PLAC concentration in the cerebrospinal fluid, measured at 3 or 6 h, was below the limit of detection in all four patients with no meningeal involvement. This study showed low but persistent levels of PLAC in plasma and tissues, with a continuous release of small amounts of ara-C, which demonstrated antitumor activity in patients with hematologic malignancies.This study was supported in part by Grants-in-Aid from the Ministry of Health and Welfare (62-18 and 63-3), Japan     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels 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/m² 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/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² 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 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/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.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     

Pharmacokinetics of high-dose etoposide after short-term infusion

Summary The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m² divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m² cytosine arabinoside (ara-C), 300 mg/m² carmustine (BCNU), or 1,200 mg/m² carboplatin. Plasma etoposide concentrations were determined by²⁵²Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629g min ml^–1 (normalized to a dose of 100 mg/m²); volume of distribution at steady state (Vd_ss), 6.6±1.2l/m²; and clearance (CL), 20.4±2.4 ml min^–1 m^–2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m²). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 g/ml, all patients exhibited undelayed hematopoietic reconstitution.     

The pharmacokinetics of the quinazoline antifolate ICID 1694 in mice and rats

Summary N-(5-[N-(3,4-Dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-l-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitorN ¹⁰-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be an active anticancer agent in early clinical studies, but its use was limited by its relative insolubility at physiological pH. ICI D1694 has been shown to be a more active anticancer agent than CB 3717 in model systems, and it is devoid of the acute renal toxicity associated with the administration of the latter drug to mice. In the present study, the pharmacokinetics of ICI D1694 were studied in both mice and rats using reverse-phase HPLC. In rats, ICI D1694 clearance (CL) conformed to a two-compartment open model and was rapid (CL=10.7 ml min^–1 kg^–1,t1/2=30 min). Excretion was mainly biliary (65% of the delivered dose in 4 h vs 12% in urine) in the rat following a 100-mg/kg i.v. bolus. A high degree of protein binding was seen in rat plasma (90% over the range of 20–100 m). In mice, ICI D1694CL=27 ml min^–1 kg^–1 andt1/2=30 min following 100 mg/kg i.v., which was significantly faster than CB3717 clearance (CL=6 ml min^–1 kg^–1,t1/2=93 min). ICI D1694 was fully bioavailable following i.p. administration (AUC=3.73 mg ml^–1 min i.v. 4.03 mg ml^–1 min i.p.), but its bioavailability following oral administration appeared to be low (approximately 10%–20%). Tissue distribution and excretion studies in mice suggested that biliary excretion predominated, confirming the results obtained in rats. Following an i.v. dose of 500 mg/kg ICI D1694 in mice, drug was detectable at 24h, suggesting the presence of a third phase of plasma clearance. The initial HPLC assay could not detect this third phase following a dose of 100 mg/kg; hence, a more sensitive assay was developed that includes a solid-phase extraction step. The latter assay was used to define the third phase of ICI D1694 clearance in mice, and preliminary studies demonstrated a terminal half-life of 6.5±2.7 h.These studies were supported by the UK Cancer Research Campaign and the British Technology Group     

Pharmacokinetics of PEG-l-asparaginase and plasma and cerebrospinal fluidl-asparagine concentrations in the rhesus monkey

The pharmacokinetics of the polyethylene glycol-conjugated form of the enzymel-asparaginase and the depletion ofl-asparagine from the plasma and cerebrospinal fluid (CSF) following an i.m. dose of 2500 IU/m² PEG-l-asparaginase was studied in rhesus monkeys. PEG-l-asparaginase activity in plasma was detectable by 1 h after injection and maintained a plateau of approximately 4 IU/ml for more than 5 days. Subsequent elimination from plasma was monoexponential with a half-life of 6±1 days. Plasmal-asparagine concentrations fell from pretreatment levels of 14–47 M to <2 M by 24 h after injection in all animals and remained undetectable for the duration of the 25-day observation period in four of six animals. In two animals, plasmal-asparagine became detectable when the PEG-l-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSFl-asparagine levels ranged from 4.7 to 13.6 M and fell to <0.25 M by 48 h in five of six animals. CSFl-asparagine concentrations remained below 0.25 M for 10–14 days in four animals. One animal had detectable CSFl-asparagine concentrations within 24 h and another had detectable concentrations within 1 week of drug administration despite a plasma PEG-l-asparaginase activity profile that did not differ from that of the other animals. These observations may be useful in the design of clinical trials with PEG-l-asparaginase in which correlations among PEG-l-asparaginase pharmacokinetics, depletion ofl-asparagine, and clinical outcome should be sought.     

Effects of pirarubicin,an antitumor antibiotic,on the cardiovascular system

Summary In the present study we examined the effects of pirarubicin [(2R)-4-0-tetrahydropyranyladriamycin, THP] on a cardiovascular system. An injection of THP (0.39–3.13 mg/kg, i. v.) reduced the mean blood pressure and caused an increase in the respiratory air rate in anesthetized rats. At 1.5×10^–6–1.5×10^–5 m, THP markedly relaxed a contraction induced by 10^–7 m norepinephrine in rat aorta with endothelium but not in that without endothelium. At a dose of 0.02–0.5 mg, THP produced an increase in the contractile force and the perfusion flow of isolated perfused guinea pig hearts. At a higher concentration (4.5×10^–5–1.5×10^–4 m), it produced a slight increase in the contractile force of the left atria in guinea pigs. This positive inotropic action of THP was inhibited by diphenhydramine (10^–6–5×10^–5 m), chlorpheniramine (3×10^–7–3×10^–5 m), and tripelennamine (3×10^–7–3×10^–5 m) but not by propranolol (10^–6 m), cimetidine (10^–5 m), diltiazem (10^–6 m), or ryanodine (10^–8 m). THP given i. v. at 2.5 mg/kg elevated the plasma histamine level in anesthetized dogs. From these data, we conclude that THP mainly relaxed the rat aorta in the presence of endothelium and that at higher concentrations, it increased the contractile force in the cardiac muscle, probably mediated through the release of histamine.     

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion

Summary A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m² per day for 5 days and repeated every 21–28 days. The patient population had a median age of 55 years (range 38–76) and a median Karnofsky performance status of 80 (range 60–100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/l (range 100–4800) in 8 heavily pretreated patients treated at 350 mg/m² per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m² and had WBC nadirs of 800/l and 600l. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m² per day, nadir 85000/l). Neither hyponatremia nor symptomatic hypoosmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m² per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09–6.79 g/ml. Steady state was achieved in 14.5±5.9 h (mean ±SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t^1/2 of 5.3±3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543±150 g/ml h and reflected a cyclophosphamide total-body clearance (CL_TB) of 103±31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6–4.3 g/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3%±7.6% and 15.1%±2.0% of the administered daily dose, respectively. The t^1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m² as an i.v. bolus. The AUC of alkylating activity associated with the 5-day continuous infusion of cyclophosphamide is about three times greater than the AUC of alkylating activity calculated after a 1500-mg/m² bolus dose of cyclophosphamide. Daily urinary excretions of cyclophosphamide and alkylating activity associated with the 5-day continuous infusion schedule are similar to those reported after bolus doses of cyclophosphamide.     

Plasma and Cerebrospinal Fluid Pharmacokinetics of Intravenous Temozolomide in Non-human Primates

Temozolomide is a prodrug that undergoes spontaneous chemical degradation at physiologic pH to form the highly reactive alkylating agent, methyl-triazenyl imidazole carboxamide (MTIC). In clinical trials, temozolomide has activity in gliomas and is approved for recurrent anaplastic astrocytoma. We, therefore, studied the penetration of temozolomide into the cerebrospinal fluid (CSF) as a surrogate for blood–brain barrier penetration in a non-human primate model. Three Rhesus monkeys with indwelling Ommaya reservoirs received 7.5mg/kg (150mg/m²) of temozolomide as a 1h intravenous infusion. Frequent blood and CSF samples were obtained over 24h, plasma was immediately separated by centrifugation at 4°C, and plasma and CSF samples were acidified with HCl. Temozolomide concentration in plasma and CSF was measured by reverse-phase high-pressure liquid chromatography. Plasma temozolomide concentration peaked 0.5h after the end of the infusion and was 104±3M. The mean peak CSF temozolomide concentration was 26±4M at 2.5h. The mean areas under the temozolomide concentration–time curves in plasma and CSF were 392±18 and 126±18Mh, respectively, and the CSF:plasma ratio was 0.33±0.06. Clearance of temozolomide was 0.116±0.004l/kg/h, and the volume of distribution at steady state was 0.254±0.033l/kg. In this non-human primate model, temozolomide penetrated readily across the blood–brain barrier. These findings are consistent with the activity of temozolomide in brain tumors.     

Clinical pharmacokinetics of 3-deazaguanine

Summary 3-Deazaguanine (3DG), an antipurine antimetabolite, has recently completed a phase I clinical trial at this Institute. The drug was given on a dailyx5 schedule by i.v. infusion over 0.25–2.16 h. The pharmacokinetics of 3DG during 16 courses were studied in 12 patients at doses of 200–800 mg/m². 3DG in plasma was measured by an isocratic reverse-phase high-performance liquid chromatographic (HPLC) procedure carried out on IBM phenyl columns at 40° C using 10mM phosphate buffer (pH 7) as the mobile phase and detection at 300 nm. Plasma decay of 3DG was biexponential in all patients. The AUC correlated linearly with dose at 200–600 mg/m² but deviated from linearity at doses>600 mg/m². The drug was cleared rapidly from plasma; at doses of 200–600 mg/m², the mean plasma clearance was 61.64±9.97 l/h and the mean terminal-phase elimination half-life was 1.6±0.6 h. The steady-state volume of distribution (98.8±29.1 l) and distribution coefficient (1.24±0.39 l/kg) indicated extensive tissue distribution for the drug. No statistically significant difference was observed between the pharmacokinetics of 3DG on day 1 and that on day 4 as evaluated in three patients for whom complete plasma data were available on both days.     

Pharmacokinetics of Amonafide in dogs

Summary Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. [2] has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m²) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t_1/2, of Amonofide was 2.4±0.4 min, the intermediate t_1/2, 26.8±3.7 min, and the terminal t_1/2, 21.7±4.0 h. the peak plasma concentration achieved was 6.3±1.7 g/ml. The average apparent volume of distribution was 12.84±0.541/kg, and the total clearance was 0.56±0.161/kg/h. In 24 h, 9.5%±0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4%±1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20–25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The and plasma t_1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.     

In vitro evaluation of a novel chemotherapeutic agent,adozelesin, in gynecologic-cancer cell lines

Summary Adozelesin is a derivative of an extremely cytotoxic compound, CC1065. This entirely new class of drug binds preferentially to DNA and facilitates alkylation reaction. In the present study, we used the adenosine triphosphate (ATP) chemosensitivity assay to compare the cytotoxic potency of Adozelesin with that of common chemotherapeutic agents in ten gynecologic-cancer cell lines. Flow cytometry was also used to study its effects on cell-cycle kinetics. The mean drug concentrations required to produce a 50% reduction in ATP levels as compared with controls [IC₅₀] were: Adriamycin, 0.17±0.06 m; 4OH-Cytoxan, 18±3 m; cisplatin, 17±7 m; 5-fluorouracil, 183±116 m; and Adozelesin, 11.0±5.4pm. Thus, Adozelesin was 10⁴–10⁷ times more potent than Adriamycin, cisplatin, 5-fluorouracil, and Cytoxan. Cell kinetics studies revealed significant S and G2 blocks such as those previously reported for other alkylating agents.Supported in part by an American Cancer Society Clinical Oncology Fellowship and an American Cancer Society/Florida Division Startup Grant (both awarded to H. N. N.)     

Daunorubicin and daunorubicinol pharmacokinetics in plasma and tissues in the rat

Recent evidence suggests that 13-hydroxy metabolites of anthracyclines may contribute to cardiotoxicity. This study was designed to determine the pharmacokinetics of daunorubicin and the 13-hydroxy metabolite daunorubicinol in plasma and tissues, including the heart. Fisher 344 rats received 5 mg kg^–1 daunorubicin i.v. by bolus injection. Rats were killed at selected intervals for up to 1 week after daunorubicin administration for determination of concentrations of daunorubicin and daunorubicinol in the plasma, heart, liver, kidney, lung, and skeletal muscle. Peak concentrations of daunorubicin were higher than those of daunorubicinol in the plasma (133±7 versus 36±2 ng ml^–1;P<0.05), heart (15.2±1.4 versus 3.4±0.4 g g^–1;P<0.05), and other tissues. However, the apparent elimination half-life of daunorubicinol was longer than that of daunorubicin in most tissues, including the plasma (23.1 versus 14.5 h) and heart (38.5 versus 19.3 h). In addition, areas under the concentration/time curves (AUC) obtained for daunorubicinol exceeded those found for daunorubicin in almost all tissues, with the ratios being 1.9 in plasma and 1.7 in the heart. The ratio of daunorubicinol to daunorubicin concentrations increased dramatically with time from <1 at up to 1 h to 87 at 168 h in cardiac tissue. Thus, following daunorubicin injection, cumulative exposure (AUC) to daunorubicinol was greater than that to daunorubicin in the plasma and heart. If daunorubicinol has equivalent or greater potency than daunorubicin in causing impairment of myocardial function, it may make an important contribution to the pathogenesis of cardiotoxicity.     

Deoxypyrimidine-induced inhibition of the cytokinetic effects of 1-β-d-arabinofuranosyluracil

Summary Ara-U-induced S-phase accumulation and the interaction between high concentrations of ara-U (HiCAU) and ara-C were investigated in L1210 leukemia cells in vitro. Treatment of exponentially growing L1210 murine leukemia cells with ara-U (200–1000 m) for 48 h caused a dose-dependent accumulation of cells in the S-phase. The extent of this ara-U-induced S-phase accumulation correlated with ara-U incorporation into DNA and with increases of up to 172% and 464% in the specific activities of deoxycytidine kinase and thymidine kinase, respectively, over control values. Metabolism of 1 m ara-C following the exposure of cells to ara-U (1mm) resulted in 4.5 pmol ara-C DNA/mg protein vs 2.1 pmol/mg protein in control cells. Although 48-h exposure of cells to 200 and 400 m ara-U is not cytotoxic, it enhances the cytotoxicity of ara-C (10–100 m) 4- to 10-fold. Ara-U-induced S-phase accumulation is inhibited by deoxypyrimidine nucleosides but not by pyrimidine or deoxypurine nucleosides. Some of the ara-U and ara-C concentrations used in this study are achievable in clinical practice, and ara-U/ara-C interactions may explain in part the unique therapeutic utility of high-dose ara-C.Abbreviations ara-C 1--d-arabinofuranosylcytosine - ara-U 1--d-arabinofuranosyluracil - ara-CTP 1--d-arabinofuranosylcytidine triphosphate - HiDAC high-dose ara-C - HiCAU high concentrations of ara-U - dCTP deoxycytidine triphosphate - HiDAU high-dose ara-U - FiTC Fluoroisothiocyanate - dUDP deoxyuridine diphosphate - dUTP deoxyuridine triphosphate - dTTP thymidine triphosphate - BrdUrd bromodeoxyuridine - dCyd kinase deoxycytidine kinase Supported in part by grant CH-35H from the American Cancer Society, by Public Health Service grant CA-12197 from the National Cancer Institute, National Institutes of Health, and by the Gaston Cancer Society     

Uridine pharmacokinetics in cancer patients

Summary The availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-l-aspartic acid (PALA) and acivicin by virtue of the cell's ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57±0.28 and 1.79±0.62 min and a terminal half-life of 17.5±7.3 min. The volume of distribution was 481±70 ml/kg, and the plasma uridine clearance was calculated to be 1.70±0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32±0.58 M, and that in the bone marrow plasma was 10.44±5.06 M. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow.Supported by grants CA 23334 and CA 23100 from the NCI and a grant from Boehringer Ingelheim Ltd. Presented as an abstract at the American Association for Cancer Research Meeting in Los Angeles, CA, May 7–10, 1986. This research is conducted in part by the Clayton Foundation for Research, California Division. Dr. Howell is a Clayton Foundation Investigator     

Pharmacokinetics of ara-C and ara-U in plasma and CSF after high-dose administration of cytosine arabinoside

Summary Cytosine arabinoside (ara-C) and uracil arabinoside (ara-U) levels were measured in the plasma, cerebrospinal fluid (CSF), and urine of 10 patients exhibiting primary central nervous system lymphoma who received 31 infusions of high-dose ara-C (3 g/m²) as part of their treatment regimen. Peak plasma and CSF ara-C levels were 10.8 and 1.5 g/ml, respectively. Ara-C was cleared more rapidly from plasma than from CSF. Ara-U appeared rapidly in both plasma and CSF, reaching a peak that was 10 times higher than the corresponding ara-C concentration (104 and 11.2 g/ml, respectively). Only 4%–6% of the dose was excreted unchanged in the urine, but 63%–73% of it appeared as ara-U within the first 24 h. The presence of leptomeningeal lymphoma did not affect the CSF level of ara-C or ara-U.Supported in part by the Don Monti Memorial Research Foundation     

Pharmacokinetics and antitumor activity of a new platinum compound,cis-malonato[(4R,5R )-4,5-bis(aminomethyl)-2-isopropyl- 1, 3-dioxolane]platinum(II), as determined by ex vivo pharmacodynamics

The pharmacokinetics and ex vivo pharmacodynamics studies oncis-malonato[(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC₀) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72±2.74 g h ml^–1 (mean ± SD), with an initial half-life of 0.37±0.20 h, a terminal half-life of 2.19±0.93 h, a total clearance of 16.83±4.76 ml min^–1 kg^–1, and a steady-state volume of distribution of 1.57±0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P<0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.     

Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit

Summary Doxorubicin is metabolized extensively to doxorubicinol by the ubiquitous aldoketoreductase enzymes. The extent of conversion to this alcohol metabolite is important since doxorubicinol may be the major contributor to cardiotoxicity. Aldoketoreductases are inhibited in vitro by phenytoin. The present study was conducted to examine the effect of phenytoin on doxorubicin pharmacokinetics. Doxorubicin single-dose pharmacokinetic studies were performed in 10 New Zealand White rabbits after pretreatment with phenytoin or phenytoin vehicle (control) infusions in crossover fashion with 4–6 weeks between studies. Infusions were commenced 16 h before and during the course of the doxorubicin pharmacokinetic studies. Phenytoin infusion was guided by plasma phenytoin estimation to maintain total plasma concentrations between 20 and 30 g/ml. Following doxorubicin 5 mg/kg by i.v. bolus, blood samples were obtained at intervals over 32 h. Plasma doxorubicin and doxorubicinol concentrations were measured by HPLC. The mean plasma phenytoin concentrations ranged from 17.4 to 33.9 g/ml. Phenytoin infusion did not alter doxorubicin pharmacokinetics. The elimination half-life and volume of distribution were almost identical to control. Clearance of doxorubicin during phenytoin administration (60.9±5.8 ml/min per kg, mean±SE) was similar to that during vehicle infusion (67.5±5.4 ml/min per kg). Phenytoin administration was associated with a significant decrease in doxorubicinol elimination half-life from 41.0±4.8 to 25.6±2.8 h. The area under the plasma concentration/time curve (AUC) for doxorubicinol decreased significantly from 666.8±100.4 to 491.5±65.7 n.h.ml^-1. These data suggest that phenytoin at clinically relevant concentrations does not alter the conversion of doxorubicin to doxorubicinol in the rabbit. The reduction in the AUC for doxorubicinol caused by phenytoin appears to be due to an increased rate of doxorubicinol elimination. Phenytoin or similar agents may have the effect of modifying doxorubicinol plasma concentrations by induction of doxorubicinol metabolism rather than by inhibition of aldoketoreductase enzymes.     

Pharmacokinetics of acridine-4-carboxamide in the rat,with extrapolation to humans

Summary The pharmacokinetics ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) were investigated in rats after i. v. administration of 18, 55 and 81 mol/kg [³H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (±SD) model-independent pharmacokinetic parameters were; clearance (Cl), 5.3±1.1 1 h^–1 kg^–1; steady-state volume of distribution (Vss), 7.8±3.0 l/kg; mean residence time (MRT), 1.5±0.4 h; and terminal elimination half-life (t _1/2Z), 2.1±0.7 h (n=10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1–8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05–0.10; 95% confidence limits) 1 h^–1 kg^–1 and a V_ss value of 0.63 (range, 0.2–1.1) l/kg for total drug concentrations in humans.     

Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice

Purpose The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration.Methods Mice were treated with 500 mg.kg^–1 monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg^–1 orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection.Results After i.v. administration the AUC_{0–120 min} values of monoHER in plasma and heart tissue were 20.5±5.3 mol.min.ml^–1 and 4.9±1.3 mol.min.g^–1 wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 M monoHER was maintained from 5 to 15 min after administration. The AUC_{0–120 min} values of monoHER were 6.1±1.1 mol.min.ml^–1 and 1.6±0.4 mol.min.g^–1 wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 M) between 10 and 20 min after administration. The AUC_{0–120 min} values of monoHER in plasma, heart, liver and kidney tissues were 8.0±0.6 mol.min.ml^–1, 2.0±0.1, 22.4±2.0 and 20.5±5.7 mol.min.g^–1, respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability.Conclusions MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the C_max was 131 M and the AUC was 6.3 M.min. These values will be considered endpoints for the clinical phase I study of monoHER.