Pharmacological disposition of 1,4-bis (2-[(2-hydroxyethyl)amino]-ethylamino)-9,10-anthracenedione diacetate in the dog.

1,4-Bis (2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (NSC 287513) (HAQ) may be selected for clinical trial based on its activity against a number of transplantable rodent tumors. Using a high-pressure liquid chromatograph assay, we have studied the pharmacological fate of HAQ in beagles. After i.v. administration of HAQ at 15 mg/kg (300 mg/sq m), the initial plasma t1/2 of the agent was 9.4 min, and the terminal t1/2 was 115.2 min. A maximal plasma concentration of 24.9 mg of HAQ per liter was attained. A high plasma clearance of 23.5 ml/kg/min was observed in these animals. The extrapolated apparent volume of distribution was 693.7 ml/kg, comparable to that of antipyrine in the dog. In 5 hr, 24.0% of the administered HAQ has been excreted in the urine unchanged, and a trace of a metabolite was detected, amounting to less than 2% of the UV-absorbing (254 nm) materials. However, hepatobiliary excretion constituted the primary route of drug elimination since 39.5% of the dose was found in the bile during the same period. An extraction procedure has been developed to quantify HAQ in tissue homogenates with 75 to 80% recovery. At autopsy, 5 hr after dosing, drug distribution in terms of percentage of the dose administered is as follows: liver, 7%; kidneys, 3.5%; pancreas, 3.1%; small intestine, 1.5%; stomach, 1.3%; spleen, 0.7%; lungs, 0.5%; heart, 0.4%; large intestine, 0.4%; and brain, 0.2%.

Induction of DNA strand breaks and cross-links by 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone in Chinese hamster ovary cells.

The DNA-damaging effects of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (AZQ) in Chinese hamster ovary cells were investigated. As determined by alkaline elution, DNA strand breaks were observed in cells treated with 50 microM AZQ for 2 hr. The single-strand break frequency was 31.3 +/- 5.3 (S.D.) rad equivalents. Strand breaks could also be detected at lower drug concentration if proteinase K treatment was included before DNA elution. In comparison, DNA cross-links were apparent in cells treated with as low as 6.25 microM AZQ. The cross-linking frequencies were 39.7, 124.3, 230.3, and 625.1 rad-equivalents for 6.25, 12.5, 25, and 50 microM AZQ, respectively. Both DNA-DNA and DNA-protein cross-links in AZQ-treated cells were revealed by the proteinase K assay. The DNA strand breaks induced by AZQ were rapidly rejoined within 1 hr after drug removal. DNA interstrand cross-links increased within the first 6 hr of postincubation and then slightly decreased by 12 hr, and most of the cross-links disappeared after cells were allowed to recover for 24 hr. DNA-protein cross-links were immediately formed during the drug treatment period and were gradually decreased after drug removal.

Clinical pharmacokinetics of 5-methyltetrahydrohomofolate.

DL-N5-Methyltetrahydrohomofolate (MTHHF; NSC-139490; N- [(4-[(2-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6- pteridinyl)ethyl) amino) benzoyl)] -L-glutamate), a new folate antagonist of relatively low toxicity, is active against experimental tumor systems resistant to methotrexate and consequently now in clinical trial. We investigated its clinical pharmacokinetics in six patients; four of them received by rapid i.v. infusion tracer doses of [N5-methyl-14C]MTHHF ranging from 13 to 16 mg/sq m, and 2 received 150 mg/sq m; the total radioactivity dose was 100 to 200 mu Ci/patient. MTHHF was assayed by radiochemical and chromatographic techniques. The elimination of MTHHF from the plasma followed a triexponential pattern, with a harmonic mean initial half-life of 20.1 min, an intermediary half-life of 4.5 hr, and a terminal half-life of 74.6 hr. The apparent volume of distribution was 1.6 liters/kg, suggesting rapid and extensive tissue binding. This, together with the low total clearance of 0.2 ml/kg/min, contributed to the long half-life of this agent. Although 68% of the administered dose was excreted in the urine on the first day, only an additional 1% was excreted on the ensuing 3 days. In the two patients who received the higher dose, very little MTHHF was found in the cerebrospinal fluid. In concentrations ranging from 25 to 500 micrograms/ml, the drug was about 50% bound to plasma protein. MTHHF was not metabolized in humans as also reported in animals. These results suggest that MTHHF is excreted in the bile to certain extent. Moreover, since it tends to localize and persist in the body, to forestall cumulative toxicity, frequent administration of this agent should be undertaken only with caution.

Clinical pharmacokinetics of vinblastine by continuous intravenous infusion.

Vinblastine (VLB) is moderately active clinically against advanced breast cancer. Since VLB is extensively taken up by platelets and thus only partially available to tumor cells, to enhance the therapeutic index of VLB we have therefore administered this agent by continuous i.v. infusion to patients with advanced breast cancer. In conjunction with the clinical trial, we conducted pharmacokinetic studies of generally tritiated VLB, using radiochemical and chromatographic techniques. The elimination of VLB from the plasma of patients who received it by 5-day i.v. infusion at 1 to 2 mg/sq m daily was biphasic. In four patients who achieved partial remission, the average plasma half-life of VLB during the terminal phase was 29.4 +/- 14.6 days, with a total clearance of 36 +/- 8 ml/kg/hr, and a steady-state apparent volume of distribution of 28.1 +/- 8.5 liters/kg. However, in three patients whose disease merely stabilized, the plasma half-life was 6.4 +/- 1.6 days, the total clearance was 137 +/- 2.9 ml/kg/hr, and the volume of distribution was 33.0 +/- 11.6 liters/kg. In contrast, in five patients with refractory disease, these parameters were 2.3 +/- 0.3 days, 541 +/- 124 ml/kg/hr, and 37.6 +/- 8.6 liters/kg. Since the apparent volumes of distributions at steady state did not differ significantly among these three groups, whereas the values of the total clearance were markedly dissimilar, the plasma half-lives of VLB were significantly shorter in patients not responsive to continuous infusion therapy with this drug. Although the number of patients studied was small, it nevertheless appears that favorable clinical response of patients with advanced breast cancer is associated with slow total clearance of the drug.

A comparison of the lethal effects of three nitrosourea derivatives on cultured human lymphoma cells.

The cellular effects of three nitrosourea derivatives were investigated on a human lymphoma cell line. The three drugs show similar threshold-type dose-response survival curves on asynchronous cells treated for 1 hr. Longer incubation periods result in rapid biological degradation for 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, whereas, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, remains cytotoxic after about 24 hr. Important differences were noted with respect to cell cycle dependency. The 1,3-bis(2-chloroethyl)-1-nitrosourea was more effective in early S and in G2 phase, whereas both 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea were more effective in early S. 1,3-bis(2-chlrorethyl)-1-nitrosourea exerted a considerable degree of killing in G1. Cells were unable to recover from priming damage induced by all 3 nitrosourea derivatives. No synergistic effects were observed in combination with vitamin A.

Cell cycle phase-specific cytotoxicity of the antitumor agent maytansine.

The objective of this investigation was to study the effects of maytansine on the cell cycle kinetics of HeLa cells. The results of this study indicate that maytansine is a very potent mitotic inhibitor and that it has no effect on macromolecular synthesis. Maytansine-induced cytotoxicity was dependent upon the position of the cell in the cell cycle. Mitotic and G2 cells are most sensitive to this agent, while G1 phase cells are the most resistant, with S-phase cells being intermediate. Small (0.82 X 10(-8) M) fractionated doses given at an interval of 8 hr have been found to be more cytotoxic than was a large (1.63 X 10(-8) M) single dose. In evaluating the drug combinations, we observed that the schedule in which 1-beta-D-arabinofuranosylcytosine treatment was followed by maytansine treatment exhibited greater cell kill than the reverse sequence. No schedule-dependent effects were observed when maytansine was tried in combination with Adriamycin.

Pharmacology of pentamethylmelamine in humans.

A rapid, specific high-pressure liquid chromatographic assay was used to study the pharmacology of pentamethylmelamine in 21 patients (28 infusions) receiving 80 to 1500 mg/sq m. In patients with normal liver function, pentamethylmelamine was rapidly cleared from the plasma with a terminal half-life of 2.2 hr. Abnormal liver function tended to correlate with increased half-life and reduced total clearance. In addition, increased neurological toxicity was associated with hepatic abnormalities. The N2,N2,N4,N6-tetramethylmelamine, N2,N4,N6-trimethylmelamine, dimethylmelamine, and monomethylmelamine metabolites were detected in plasma. The terminal plasma half-lives of these metabolites increased with decreasing number of methyl group. With liver dysfunction, the plasma clearance of these metabolites also decreased and central nervous system toxicity increased. Although the antitumor activity of pentamethylmelamine is thought to be mediated by the intermediate hydroxymethyl metabolites produced by hepatic microsomal oxidation or by the formaldehyde generated, the neurological toxicity appears to depend upon the pharmacokinetics of the drug and its demethylated metabolites.

Pharmacokinetics of [14C]methylglyoxal-bis-guanylhydrazone) in patients with leukemia.

Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

Comparative structure-genotoxicity study of three aminoanthraquinone drugs and doxorubicin.

Two aminoanthraquinone analogs 1,4-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (HAQ) and 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino]-9,10-anthracenedione (DHAQ) have been shown to possess similar therapeutic activities against experimental tumors but different toxicities to the animals. In this study, the genotoxic effects of these two drugs and a new analog, 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino]-9,10-anthracenedione diacetate, were analyzed by using mammalian cell cytogenetic assays (chromosome breakage and sister chromatid exchanges) as well as bacterial mutagenesis assays. The experimental therapeutic activities of these drugs in vivo correlated well with their in vitro genetic toxicities as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage. DHAQ was also more genotoxic than Adriamycin. In cytogenetic assays, the activities of all drugs were reduced to different degrees in the presence of a S-9 metabolic system. Discrepancies were observed between results obtained from cytogenic assays and those from mutagenesis assays. Whereas DHAQ was most active in cytogenetic studies, Adriamycin was most mutagenic or toxic. HAQ was least active cytogenetically, and this activity was not changed appreciably in the presence of metabolic enzymes. However, it was metabolically activated to a bacterial mutagen. Our studies suggest that the cytogenetic and mutagenesis assays may be sensitive to the activities of different agents and of different moieties of the same agent. The application of short-term in vitro assays to identify the chemical structures responsible for genetic toxicity and for therapeutic activities in vivo may lead to the better understanding of drug activities and to the development of more effective drugs.

Human pharmacokinetics of a new acridine derivative, 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992).

The clinical pharmacology of 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine) was studied, utilizing [9-14C]amsacrine i.v. in 19 patients with disseminated neoplasms. The mean terminal plasma half-life for total 14C ranged from 34 hr in patients with normal organ function to 46 hr in patients with severe liver disease. For unchanged amsacrine, the mean values of plasma half-life were 7.4 and 17.2 hr for patients with normal and abnormal liver function, respectively. The plasma half-lives of 14C were prolonged, while those for unchanged amsacrine appeared to be normal in patients with renal dysfunction. The mean 72-hr cumulative urinary excretion of total 14C varied from 35% in normal patients to 49% in patients with severe liver disease, while patients with renal disease excreted only 2 to 16%. In comparison, the urinary excretion of unchanged amsacrine was 12, 20 and 2% of the administered dose, respectively, in these same patients. Amsacrine biliary excretion studied in two patients showed about 8 and 36% of the administered radioactivity excreted in the bile in 72 hr, with less than 2% as unchanged amsacrine. Cerebrospinal fluid concentrations of amsacrine were below 2% of the simultaneous plasma levels in three patients. Impaired amsacrine drug clearance was frequently associated with liver dysfunction. Patients with impaired amsacrine drug clearance experienced the most severe clinical toxicity. Hepatic metabolism and biliary excretion appear the most important routes for amsacrine elimination. Renal elimination, although less important, is significant in patients with severe kidney dysfunction. To avoid excessive clinical toxicity, initial dose reductions of 30 to 40% are recommended for patients with severe liver or renal disease or for those who have pharmacologically documented impaired drug clearance.

Human urinary metabolites of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftoraful).

Two hydroxylated metabolites were isolated from the urine of a patient who had received ftorafur (5 g/sq m). These metabolites were identified by mass spectrometry and nuclear magnetic resonance spectroscopy as trans-3'- and cis-4'-hydroxyftorafur. The compounds were not converted to 4-fluorouracil when incubated in plasma, base (pH 9), or water. Because of their stability, it is unlikely that these metabolites are in vivo precursors of 5-fluorouracil. There are indications that less stable, unisolatable, hydroxylated ftorafur derivatives are intermediates in the conversion of ftorafur to 5-fluorouracil.

Pharmacological disposition of N-(phosphonacetyl)-L-aspartate in humans.

The pharmacological disposition of N-(phosphonacetyl)-L-aspartate (PALA), an antitumor transition state analog currently in clinical trial, has been studied in 19 patients after i.v. administration of the agent at doses ranging from 800 to 5000 mg/sq m; PALA in biological specimens was assayed enzymatically, advantage being taken of its inhibition of L-aspartate carbamoyltransferase (EC 2.1.3.2) PALA disappeared from plasma biexponentially, with an average terminal t 1/2 of 5.3 hr. It was excreted in the urine unchanged; the 24-hr cumulative excretion was 85% of the administered dose. The average total clearance was 1.60 ml/kg/min and was linearly related to creatinine clearance, suggesting that in humans PALA is essentially cleared by glomerular filtration. The apparent volume of distribution of PALA was 309 ml/kg, approximately the sulfate space in humans. PALA penetrated into the central nervous system only to a limited extent. Tumor L-aspartate carbamoyltransferase activity was also measured before and 1.5 hr to 6 days after PALA administration; in all eight studies, a notable decrease in enzyme activity was observed.

Disposition and metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) in humans.

The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 microgram/ml) for at least 48 hr after FT administration. The concentrations of FUra derived from the administration of FT were considerably greater than were those achieved by constant infusion of FUra at the maximal tolerated dose of 1.1 g/sq m without causing unacceptable mucositis. The cumulative urinary excretion was 20% of the administered dose in 24 hr. FT underwent in vivo biotransformation to 2 hydroxytetrahydrofuranyl-5-fluorouracil derivatives in addition to anabolites and catabolites of FUra. High concentrations of FT and FUra were present in the cerebrospinal fluid, which could account for the severe central nervous system toxicity of FT at high doses. We conclude that the antitumor activity of FT is partially attributable to its slow release of FUra.

Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans.

Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

Pharmacological and biochemical interactions of N-(phosphonacetyl)-L-aspartate and 5-fluorouracil in beagles.

N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorouracil (FUra) are both antimetabolites that affect the biosynthetic pathways of pyrimidines. To determine whether these two drugs exhibit synergistic pharmacological or biochemical interactions, we determined the pharmacological and biochemical parameters of PALA and [14C]FUra in 14 beagle dogs which received i.v. bolus administrations of either the single agents or the drug combination. The pharmacokinetic parameters of PALA (four dogs, 20 mg/kg) in plasma, cerebrospinal fluid, and urine were not changed by FUra (10 mg/kg, 30 min after PALA). The pharmacokinetics of [2-(14)C]FUra (six dogs, 10 mg/kg, 20 muCi/kg) was characterized by higher FUra plasma concentrations after pretreatment with PALA (20 mg/kg, 30 min before FUra); this led to a significantly larger area under the drug concentration-time curve, a decreased volume of distribution, and a reduced clearance rate and was associated with higher cerebrospinal fluid concentrations of FUra. The FUra plasma and cerebrospinal fluid half-lives, however, were not significantly altered by PALA. The biochemical determinants of PALA and FUra activity were studied in intestinal mucosa, liver, thymus, spleen, and bone marrow of four dogs. Although the activity of the target enzyme of PALA, L-aspartate carbamoyltransferase, in tissue extracts was decreased at least 50% at 18 to 24 hr after PALA administration (50 mg/kg), the uridine nucleotide pools remained remarkably stable. Intracellular FUra concentrations were not influenced by PALA. The incorporation of 5-fluorouridine triphosphate into RNA was enhanced in intestinal mucosa and liver. In other tissues, however, fluorouridine nucleotide concentrations were not affected by PALA. Free 5-fluorodeoxyuridine monophosphate had the highest concentration in liver and was detectable in all tissues, but it was not altered by PALA treatment. Our results show that the pharmacological and biochemical events after FUra exposure are marginally modulated by PALA in normal dogs. If sensitive tumors with a higher degree of interaction between the two drugs could be identified, limited toxicity to normal tissues can be expected.

Pharmacokinetics and disposition of 3-deazauridine in humans.

3-Deazauridine (3-DAU) pharmacology was studied in 20 patients who received the drug by rapid or continuous infusion. In 8 studies, the plasma clearance of 3-DAU after rapid administration was biphasic, with an average terminal t1/2 of 4.4 hr and an extrapolated volume of distribution of 0.57 liter/kg. After 5-day continuous infusion of 3-DAU, the plasma clearance was also biphasic, with an average terminal t1/2 of 21.3 hr and an extrapolated volume of distribution of 18.8 liter/kg. 2,4-Dihydroxypyridine, the aglycone of 3-DAU, was observed in plasma but not in urine of patients receiving the drug by rapid infusion. The urinary excretion of 3-DAU was low, only 7.8% 24 hr after rapid infusion and 7.2% up to 4 days after continuous infusion. Tissue distribution of 3-DAU was determined from autopsy samples of 2 patients. Not only were high levels of 3-DAU detected in the tissues studied, but 3-DAU triphosphate, the active metabolite of 3-DAU, was present in brain, lung, and liver.

Schedule-dependent synergistic cytotoxicity of arabinofuranosylcytosine with adriamycin or 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione in cultured cells.

The purpose of this study was to demonstrate that in vitro cell culture systems could serve a useful purpose in providing some guidelines in formulating drug schedules for combination cancer chemotherapy in the clinic. Using monolayer cultures of Chinese hamster ovary cells as the test system, we screened the combinations of 1-beta-D-arabinofuranosylcytosine (ara-C) + adriamycin, ara-C + 3,6 - BIS(5 - CHloro - 2 - piperidinyl) - 2,5 - piperazinedione, melphalan + 5-fluorouracil, and melphalan + ara-C as to the effect of drug sequence on the plating efficiency of these cells. Schedule-dependent therapeutic synergism was observed only when ara-C treatment was followed by either adriamycin or 3,6-bis(5-chloro-2-piperidinyl)2,5-piperazinedione but not vice versa. No synergistic effects were observed in the combination of melphalan with 5-fluorouracil or ara-C. The basis for this synergism appeared to be that ara-C was primarily acting as a synchronizing agent to set up the cells in S phase so that subsequent treatment with an S-phase-specific drug, such as adriamycin or 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione, would produce the maximum cell kill. On the other hand, the lack of synergism in the combinations of melphalan with 5-fluorouracil or ara-C was due to the lack of S-phase specificity for melphalan. On the basis of these data, we postulate that schedule-dependent synergism could be expected if the first agent renders the cells more sensitive (for example, by selectively blocking cells in one of the phases of the cell cycle) to the action of the second drug.

Penetration of 3-deazauridine into human brain, intracerebral tumor, and cerebrospinal fluid.

The antitumor agent 3-deazauridine (DAU) was administered rapidly to four patients before surgical removal of intracerebral tumor. Tumor, adjacent brain tissue, and temporalis muscle were assayed for DAU by high-pressure liquid chromatography. DAU penetrated comparably into tumor, brain, and muscle; in one patient, tissue concentrations were higher than concurrent plasma concentrations. The active metabolite 3-deazauridine 5'-triphosphate was quantitated in one tumor sample and greatly exceeded its Ki for cytidine 5'-triphosphate synthetase. DAU was also present in autopsy brain specimens from two patients treated shortly antemortem. Cerebrospinal fluid concentrations were 22.1 and 59.0%, respectively, of concurrent plasma concentrations during continuous infusion of DAU in two patients. Cerebrospinal fluid concentration was 3.1 microgram/ml 2 hr after a 30-min infusion of 1.5 g of drug per sq m and fell to 1.9 microgram/ml at 16 hr. Thus, DAU is capable of penetrating into intracerebral tumor, brain, and cerebrospinal fluid and is worthy of investigation in the treatment of intracerebral and meningeal neoplasms.

Penetration of N-(phosphonacetyl)-L-aspartate into human central nervous system and intracerebral tumor.

Cerebrospinal fluid (CSF) was obtained from five patients by lumbar puncture and from two patients by Ommaya reservoir tap after the i.v. administration of the antitumor agent N-(phosphonacetyl)-L-aspartate (PALA). PALA was quantified enzymatically by inhibition of the target enzyme, aspartate carbamoyltransferase. After a 1-hr infusion of PALA, its CSF concentration steadily rose until the eighth hr, at which time it was 12 to 40% of concurrent plasma concentration. PALA concentration then declined more gradually in CSF than in plasma, and CSF concentrations exceeded plasma concentrations by 24 hr. PALA concentration X time product in CSF was 12 to 25% of that in plasma. PALA was infused i.v. for 30 to 60 min into eight patients undergoing surgical resection if intracerebral tumors. Its concentration in intracerebral tumor was greater than or comparable to concentration in temporalis muscle in four of six patients from whom muscle was obtained. The PALA concentration in edematous brain tissue was consistently lower than the concentration in tumor or muscle. In a patient undergoing occipital lobectomy, the PALA concentration in brain was inversely proportional to the distance from the tumor. PALA reached concentrations in intracerebral tumor that appeared to be similar to concentrations reported previously in s.c. tumors, although biopsy techniques and conditions differed.

Clinical pharmacology of intraarterial cis-diamminedichloroplatinum(II).

After intraarterial (30 patients) or i.v. (seven patients) administration of cis-diamminedichloroplatinum, X-ray fluorescence spectrometry was used to measure platinum concentrations in plasma and urine. Arteries infused included hepatic (seven patients), carotid (six patients), iliac (ten patients), brachial (three patients), and femoral (four patients). All patients received i.v. mannitol. Pharmacokinetic parameters after intraarterial administration were similar to those after i.v. administration, although differences existed for different intraarterial routes of administration. Mean for all patients combined were: Co, 2.67 +/- 0.97 (S.D.) microgram/ml; t1/2 beta, 71.1 +/- 26.6 hr; clearance, 0.72 +/- 0.25 liters/hr/sq m; total volume of distribution, 45.2 +/- 17.0 liters/sq m; C x t, 167 +/- 72 mg/hr/liter; and 24-hr urinary excretion, 20 +/- 10% of the administered dose. Intrahepatic infusion of the drug was associated with a significantly lower Co (1.88 +/- 0.50 g/ml) and C x t (140 +/- 25 mg hr/liter) and significantly higher clearance (0.91 +/- 0.24 liters/hr/sq m) and volume of distribution (67.6 +/- 4.6 liters/sq m) than administration by other routes, suggesting first pass extraction of drug by liver. In addition, an apparent minor late rise in serum platinum concentration may suggest enterohepatic recirculation of drug. High fluid intake was associated with a low Co and a high volume of distribution, consistent with expansion of the central compartment by fluids. Low serum albumin (less than 3.5 g/dl) was associated with significant shortening of the t1/2 beta (50.5 +/- 21.6 hr), suggesting that the amount of unbound filterable drug may possibly be higher in patients with low serum albumin concentrations. Plasma from veins draining an infused area has a higher Co and C x t during infusion than concurrent plasma from peripheral veins. Thus, intraarterial administration of cis-diamminedichloroplatinum results in increased drug exposure of tumor in the infused area without substantially decreasing exposure of systemic tumor.