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D G Poplack

Publications and source records attributed to D G Poplack.

At least 37 records · Page 2Linked to original sources
PubMed1995

Characterization of cross-resistance to methotrexate in a human breast cancer cell line selected for resistance to melphalan.

We have demonstrated previously decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan (MelR MCF-7). Cross-resistance studies of MelR MCF-7 cells revealed that this cell line was 6.7-fold cross-resistant to methotrexate, but only 2-fold resistant to trimetrexate. Methotrexate transport studies in MelR MCF-7 cells showed a 2-fold decrease in initial methotrexate uptake and a 2-fold decrease in the Vmax for methotrexate uptake in the resistant cells. Methotrexate resistance in MelR MCF-7 cells was also associated with a decrease in non-effluxable methotrexate following incubation with radiolabeled drug for 24 hr. Characterization of intracellular methotrexate after accumulation for 24 hr demonstrated decreased levels of free methotrexate in MelR MCF-7 cells. Analysis of methotrexate polyglutamate formation in MelR MCF-7 cells indicated that the decrease in non-effluxable, non-protein-bound methotrexate was associated with a 3-fold decrease in higher order methotrexate polyglutamate formation. No difference was noted in folylpolyglutamate synthetase activity between the resistant and parental cell lines. Therefore, the observed decrease in methotrexate polyglutamate formation in MelR MCF-7 cells appeared to result from decreased availability of substrate. There was no evidence of any alteration in the amount of the catalytic activity of dihydrofolate reductase in MelR MCF-7 cells compared with parental MCF-7 (WT MCF-7) cells; moreover, the binding affinity of dihydrofolate reductase for methotrexate and the percentage of protein-bound methotrexate were similar in both cell lines. In addition, the total amounts of thymidylate synthase protein and thymidylate synthase catalytic activity in MelR MCF-7 cells were unchanged. Thus, acquired methotrexate resistance in MCF-7 cells selected for resistance to melphalan appears to result from down-regulation of methotrexate uptake.

Breast Neoplasms↗
PubMed1995

Intrathecal administration of topotecan in nonhuman primates.

The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg. Lactone and total drug concentrations were measured using a reverse-phase HPLC method with fluorescence detection. The mean peak concentrations of lactone and total drug in ventricular CSF were 83 +/- 18 microM and 88 +/- 25 microM, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3h. The mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (AUC) to lactone was 450-fold greater following intraventricular administration of 0.1 mg topotecan than after systemic intravenous administration of a 40-fold higher dose (10 mg/m2). Peak lumbar concentrations (n = 1), which occurred 2 h after intraventricular drug administration, were 0.98 microM and 2.95 microM for the lactone and total drug, respectively. A transient CSF pleocytosis was observed in one animal following intralumbar topotecan administration and in one animal following intralumbar topotecan administration. No other acute or chronic neurologic or systemic toxicities were observed following a single intraventricular dose or weekly (x4) intralumbar topotecan. Compared with systemic topotecan, intrathecal administration provided a significant pharmacokinetic advantage in terms of CSF drug exposure and did not produce any significant neurotoxicity in a nonhuman primate model. Intrathecal topotecan should be evaluated clinically as a potential alternative therapy for refractory meningeal tumors.

Animals↗
PubMed1995

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddA), didanosine, 2',3'-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 microM.h) and the 6-halogenated-ddG prodrugs (18.8 microM.h for 6-chloro-ddG, 9.3 microM.h for 6-iodo-ddG).6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.

Animals↗
PubMed1995

Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration.

PURPOSE: Intralumbar methotrexate is one of the primary therapeutic modalities for the prevention and treatment of meningeal leukemia. However, methotrexate distribution to the ventricles is limited and highly variable following intralumbar dosing, and cytotoxic concentrations of methotrexate are not always achieved or sustained in the ventricular CSF. We used a nonhuman primate model to determine the effect of body position on the caudal distribution of an intralumbar dose of methotrexate. METHODS: Methotrexate (1.0 mg) was administered by intralumbar injection to four animals, which were then immediately placed either in an upright sitting position or in a prone position for 1 hour, then upright. Each animal served as its own control and was studied in each position on at least one occasion. RESULTS: The mean peak ventricular methotrexate concentration was 0.12 mumol/L (range, 0.091 to 0.20) in animals that were immediately placed upright, compared with 2.81 mumol/L (range, 0.21 to 8.9) in animals that remained prone for 1 hour. The mean area under the concentration-versus-time curves (AUC) was 0.51 mumol/L.h (range, 0.26 to 1.1) in the upright animals and 12.0 mumol/L.h (range, 0.9 to 35.4) in the prone animals. CONCLUSION: Maintaining a prone position for 1 hour after an intralumbar dose increased the peak methotrexate concentration and drug exposure in ventricular CSF. CSF drug distribution following intralumbar therapy can be influenced by body position after the injection.

Animals↗
PubMed1995

Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule.

PURPOSE: Administration of all-trans-retinoic acid (ATRA) on a continuous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to determine if administration of ATRA on an intermittent schedule could overcome the rapid decrease in plasma drug concentration and provide repetitive periods of higher plasma drug exposure. MATERIALS AND METHODS: ATRA was administered on repetitive cycles of 7 consecutive days of drug followed by 7 days without drug. On the days of pharmacokinetic monitoring, following an overnight fast, a fixed single oral dose of 40 mg/m2 was administered and frequent plasma samples were obtained over 8 hours. Patients had pharmacokinetic studies performed on the first and seventh days of the first week, and on the first day of the third and eleventh weeks. ATRA was measured in plasma with a reverse-phase high-performance liquid chromatography (HPLC) assay. RESULTS: Plasma exposure to ATRA as measured by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mumol/L.min on day 1 to 18 +/- 4 mumol/L.min by day 7. Plasma ATRA concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to those achieved on day 1 of treatment, with mean AUCs of 177 +/- 39 and 128 +/- 30 mumol/L.min, respectively. CONCLUSION: An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. Phase II trials to evaluate the role of intermittent schedules of administration for ATRA are planned.

Acquired Immunodeficiency Syndrome↗
PubMed1994

The cytotoxicity of thioguanine vs mercaptopurine in acute lymphoblastic leukemia.

The use of mercaptopurine (MP) rather than thioguanine (TG) in the treatment of childhood acute lymphoblastic leukemia (ALL) has occurred for historical reasons, but does not have a pharmacologic basis. The purpose of this study was to begin to address whether TG would be more efficacious than MP in the treatment of childhood ALL. Preclinical cytotoxicity studies were performed using human leukemic cell lines and leukemic cells from patients with ALL. First, the concentration-survival curves for MP and TG in three human leukemic cell lines (MOLT-4, CCRF-CEM and Wilson) were determined. The second group of experiments determined the concentration-time dependence for cytotoxicity of MP and TG. The final group of experiments compared the in vitro cytotoxicity of MP to TG in leukemic cells from patients with ALL. The thiopurines displayed classical anti-metabolite cytotoxicity profiles, exhibiting a cytotoxicity threshold concentration and demonstrating an increase in cell kill with prolongation of exposure to the drug. For MP, the cytotoxicity threshold was approximately 1 microM, with maximum cytotoxicity occurring with 10 microM concentrations. For TG, the threshold was only 0.05 microM with maximum cytotoxicity occurring at 0.5 microM. Exposure to MP for more than 8 h was necessary to produce cytotoxicity, whereas exposures as short as 4 h were required for TG. Leukemic cells from children with ALL were also more sensitive to TG than to MP. The median IC50 for TG (20 microM) was significantly lower than that for MP (> or = 206 microM). The data presented here provide a strong rationale for evaluating TG in place of MP in the treatment of childhood ALL. The more direct intracellular activation pathway, higher potency, and shorter duration of drug exposure necessary for cytotoxicity all suggest that TG may have an advantage over MP.

Adolescent↗
PubMed1994

Differentiation stages of childhood acute lymphoblastic leukemias with p53 mutations.

Based upon in vitro evidence of p53 involvement in lymphoid differentiation, we assessed immunoglobulin (Ig) and T-cell receptor (TCR) genes in five acute lymphoblastic leukemias (ALLs) with, and 24 ALLs without p53 mutations to compare their genotypic stages. Using Southern blot analysis and complementarity determining region III polymerase chain reaction (CDRIII PCR), 18 cases of B-lineage ALL and 11 cases of T-ALL were studied. Of 20 specimens from 18 B-lineage ALLs, two of four with p53 mutation and two of 16 without mutation had an unrearranged Ig and TCR genotype (p = 0.16; Fisher's exact test). Of 11 cases of T-ALL, the one case with p53 mutation had a rearranged TCR and Ig genotype and a case without mutation was unrearranged. The study indicates that p53 mutation is an infrequent feature of ALL found, nonetheless, in every genotypic subset. The p53 mutations in cases that do not further rearrange may support p53 involvement in lymphoid differentiation, but the heterogeneity in differentiation stages in cases both with and without p53 mutations suggests that regulation of early lymphoid maturation is multifactorial.

Adolescent↗
PubMed1993

Desulfuration of 6-mercaptopurine. The basis for the paradoxical cytotoxicity of thiopurines in cultured human leukemic cells.

The thiopurines have a wide array of effects on purine metabolism, but the primary mechanism of cytotoxicity for both 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) appears to be incorporation of drug into DNA following conversion to the thioguanylate form. In murine leukemic cell lines exposed to a range of thiopurine concentrations in vitro, cell survival curves have displayed a phenomenon termed paradoxical cytotoxicity, defined as a decrease in cytotoxicity with increasing drug concentration. The paradoxical cytotoxicity of thiopurines has usually been attributed to concentration-dependent perturbations in the cell cycle. The present study assessed whether the paradoxical cytotoxicity of 6-MP occurred in cultured human leukemic cells, and investigated the biochemical and cell-cycle alterations occurring in these lines at thiopurine concentrations associated with the reverse of cytotoxicity. Paradoxical cytotoxicity was observed in the two human leukemic cell lines examined, but only when 6-MP concentrations exceeded 100 microM. The extent of incorporation of 6-MP metabolites into DNA as thiol-versus non-thiol-containing metabolites was analyzed by performing parallel experiments with 14C- and 35S-radiolabeled drug. With 5 microM 6-MP, approximately 50% of drug was incorporated into DNA as a thionucleotide; however, with increasing drug concentrations, the degree of thionucleotide incorporation remained unchanged or decreased, and the amount incorporated as the desulfurated metabolite (presumably adenylate or guanylate) increased. With 500 microM 6-MP, less than 10% of the drug was incorporated as the thionucleotide. Perturbations in cell cycle reflected the relative amounts of thiol- and non-thiol-containing nucleotide formed at various concentrations of 6-MP. These results suggest that thiopurines may be vulnerable to a unique mechanism of detoxification, in which a human cell can metabolize a cytotoxic drug to a comparatively potent "self-rescue" agent.

Carbon Radioisotopes↗
PubMed1993

Variability in the oral bioavailability of all-trans-retinoic acid.

BACKGROUND: Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. PURPOSE: This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. METHODS: Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. RESULTS: Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. CONCLUSION: The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.

Adenocarcinoma↗
PubMed1993

Pharmacokinetics of piroxantrone in a phase I trial of piroxantrone and granulocyte-colony stimulating factor.

Piroxantrone is an anthrapyrazole derivative with broad antitumor activity in vitro. In previous phase I trials, the dose-limiting toxicity of this agent was myelosuppression. Therefore, a phase I and pharmacokinetic study of a 1-h infusion of piroxantrone in combination with granulocyte-colony stimulating factor was conducted. In this article, we report the results of the pharmacokinetic analysis. Thirty-seven patients were studied over a dosage range of 150 to 555 mg/m2. The plasma elimination of piroxantrone was biexponential with a mean (+/- SD) t1/2 alpha of 3.2 +/- 2.7 min and a mean (+/- SD) t1/2 beta of 82 +/- 92 min. Clearance was 840 +/- 230 ml/min/m2. A limited sampling strategy was developed to allow the estimation of total drug exposure (area under the plasma concentration-time curve) from the plasma piroxantrone concentrations at 30, 60, and 120 min after the start of the infusion. The pharmacokinetic behavior of a presumed piroxantrone metabolite not previously described in plasma was also characterized. Based on in vitro cytotoxicity studies with partially purified extract of this compound, we do not believe that it contributes to the antitumor effects of piroxantrone at the concentrations observed in plasma. Finally, piroxantrone elimination was linear over the nearly 4-fold dose range studied, indicating that when dose adjustments are made, systemic drug exposure will remain predictable.

Adult↗
PubMed1993

Mechanism of resistance to cyclopentenyl cytosine (CPE-C) in Molt-4 lymphoblasts.

Cyclopentenyl cytosine (CPE-C), a carbocyclic analogue of cytidine, has preclinical antineoplastic activity against ara-C resistant murine leukemias and a broad spectrum of human tumor xenografts. CPE-C is a prodrug and requires intracellular phosphorylation to cyclopentenyl cytosine triphosphate (CPE-CTP) which depletes endogenous CTP pools. The initial step in this activation process is catalyzed by uridine/cytidine kinase. We studied the mechanism of resistance to CPE-C in a Molt-4 T-cell leukemia line made resistant to CPE-C (Molt-4R) by culturing it in the continuous presence of increasing concentrations of CPE-C. Using a tetrazolium based colorimetric assay to assess cytotoxicity, the IC90 for the parent Molt-4 cells (Molt-4WT) was 0.5 microM after a 24 hr drug exposure. In contrast, cytotoxicity was not observed at concentrations as high as 1 mM in the Molt-4R cells. Following a brief exposure to 1 microM CPE-C, parent drug could be detected intracellularly in the resistant and sensitive cell lines. However, CPE-CTP formation was reduced markedly in the resistant cell line. Measurement of the activity of anabolic and catabolic enzymes in the Molt-4WT and Molt-4R cells revealed equivalent activities of alkaline and acid phosphatases as well as cytidine and dCMP deaminase but there was a significant reduction in uridine/cytidine kinase activity in Molt-4R cells. Endogenous ribonucleotide pools and CPE-CTP pools were measured in the absence and presence of CPE-C. CTP pools were reduced markedly in Molt-4WT cells following exposure to CPE-C. However, CTP pools in Molt-4R cells exposed to 100 microM CPE-C were two times greater than in the untreated Molt-4WT cells. At high concentrations of CPE-C (10 and 100 microM), Molt-4R cells were able to generate amounts of CPE-CTP equivalent to that seen in Molt-4WT cells exposed to 1 microM CPE-C (a cytotoxic concentration of drug in Molt-4WT cells), but no cytotoxic effect was seen in Molt-4R cells. Therefore, in addition to decreased uridine/cytidine kinase activity, a second mechanism of resistance that is the result of alterations in CTP synthetase activity also appears to be operative. Elucidation of the mechanism of resistance in vitro may provide insight into the mechanism of action of the drug and potential mechanisms of resistance in vivo.

Antineoplastic Agents↗
PubMed1993

Prolongation of drug exposure in cerebrospinal fluid by encapsulation into DepoFoam.

Prolonged maintenance of a therapeutic drug concentration in the cerebrospinal fluid is required for optimal treatment of leptomeningeal leukemia or carcinomatosis with cell cycle-specific antimetabolites. The pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) encapsulated into DepoFoam (Depo/Ara-C) was studied in six rhesus monkeys after intrathecal injection into the lumbar sac. Following a single 2-mg dose, the Depo/Ara-C concentration decreased biexponentially with initial and terminal half-lives of 14.6 and 156 h, respectively. The free drug concentration remained above the reported minimal cytotoxic level of 0.1 micrograms/ml (0.4 microM) for more than 672 h (28 days). In contrast, the half-life of ara-C following an intralumbar bolus dose of unencapsulated drug in a single animal was 0.74 h. A single intrathecal injection of Depo/Ara-C can maintain a therapeutic drug concentration in the cerebrospinal fluid for a very prolonged period.

Animals↗
PubMed1993

Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.

Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in < 20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 +/- 3.7 nmol/liter and the total body clearance was 28.3 +/- 6.5 liters/h/m2. Elimination was biexponential with a t1/2 alpha of 14.4 +/- 1.8 min and a t1/2 beta of 2.9 +/- 1.1 h. The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.

Adolescent↗
PubMed1993

Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates.

Topotecan, a water soluble semisynthetic analogue of camptothecin, is a topoisomerase I inhibitor that has recently entered phase II clinical trials. Topotecan has shown significant preclinical activity in refractory murine tumors and in human tumor xenograft models. In addition, objective antineoplastic activity has been observed in recent adult phase I clinical trials. Topotecan is unstable in solution and is rapidly and spontaneously converted to a less active open ring form which predominates at physiological pH. This study was undertaken to better define the pharmacokinetic behavior of this highly unstable compound in both plasma and cerebrospinal fluid (CSF) and to measure the degree of CSF penetration of this novel antineoplastic agent. Three nonhuman primates with indwelling Ommaya reservoirs received 10 mg/m2 i.v. topotecan administered as a 10-min infusion. Frequent plasma and CSF samples were obtained and immediately extracted and assayed with a reverse phase high performance liquid chromatography assay to quantitate the concentration of topotecan (lactone). Samples were then acidified and reinjected to quantitate total drug (lactone ring plus open ring). Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 microM. Plasma disappearance of the lactone ring was biexponential with a distribution half-life (t1/2 alpha) of 22 +/- 5 min and an elimination half-life (t1/2 beta) of 1.3 +/- 0.1 h. Total body clearance of topotecan was 72.1 +/- 15.8 liters/h/m2. The volume of distribution at steady state was 88.6 +/- 33.2 liters/m2. Peak CSF concentrations of topotecan occurred at 30 min following drug administration and ranged from 0.044 to 0.074 microM. CSF disappearance paralleled that in plasma. The mean ratio of the area under the CSF concentration-time curve to that in plasma was 0.32 (range, 0.29 to 0.37). The mean CSF penetration of topotecan exceeds 30%, which is significantly greater than the penetration of most structurally similar chemotherapeutic agents. The impact of chemotherapy on the survival of patients with primary or metastatic central nervous system malignancies is very limited. Therefore, this novel antineoplastic agent is an excellent candidate for further study in patients with high risk or refractory central nervous system tumors.

Animals↗
PubMed1993

Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.

A study of chronic i.v. dosing of all-trans-retinoic acid (all-trans-RA) was performed to determine whether induction of the capacity-limited elimination process for all-trans-RA occurred with long-term drug administration. Because up-regulation of the cellular retinoic acid-binding proteins (CRABP) may act to bind all-trans-RA intracellularly, the amount of CRABP in skin biopsy samples obtained during and following the course of all-trans-RA administration was also determined. Four adult rhesus monkeys received 50 mg/m2 of all-trans-RA by bolus i.v. injection daily for 8 consecutive days and again for one additional dose following a 7-day period without drug. The plasma disappearance curve of all-trans-RA was characterized by a plateau phase, the duration of which decreased during the period of chronic drug administration, followed by a terminal exponential decay phase, which is consistent with a capacity-limited (saturable) elimination process. The Vmax of this process increased from 0.06 mumol/min on the first day to 0.17 mumol/min by the eighth day of all-trans-RA administration, consistent with induction of an enzymatic process. The amount of CRABP measured in skin biopsy specimens was rapidly induced, increasing to approximately 3-fold baseline levels by day 3 of all-trans-RA administration. It remained at this level throughout the period of chronic drug administration but diminished following the 7-day period without drug. These findings suggest that an intermittent schedule of administration for all-trans-RA has potential advantages over a continuous administration schedule. A period of time without drug administration would allow for return of plasma drug clearance toward baseline levels and down-regulation of CRABP, which could result in higher plasma drug concentrations and possibly less cytoplasmic binding of drug.

Animals↗
PubMed1993

Pharmacokinetics of PEG-L-asparaginase and plasma and cerebrospinal fluid L-asparagine concentrations in the rhesus monkey.

The pharmacokinetics of the polyethylene glycol-conjugated form of the enzyme L-asparaginase and the depletion of L-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. Plasma L-asparagine concentrations fell from pretreatment levels of 14-47 microM to < 2 microM 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, plasma L-asparagine became detectable when the PEG-L-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSF L-asparagine levels ranged from 4.7 to 13.6 microM and fell to < 0.25 microM by 48 h in five of six animals. CSF L-asparagine concentrations remained below 0.25 microM for 10-14 days in four animals. One animal had detectable CSF L-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 of L-asparagine, and clinical outcome should be sought.

Aminolevulinic Acid↗