Biomedical subjects
J O Liliemark
Publications and source records attributed to J O Liliemark.
Saturation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate accumulation in leukemia cells during high-dose 1-beta-D-arabinofuranosylcytosine therapy.
Twenty-seven patients with refractory leukemia were treated with 1-beta-D-arabinofuranosylcytosine (ara-C), 0.3 to 3.0 g/m2 as i.v. infusions over 1, 2, 4, or 24 h. The pharmacokinetics of ara-C in plasma and its 5'-triphosphate (ara-CTP) in leukemic cells from peripheral blood were studied after a single infusion of 3 g/m2 over 2 h in 13 patients. Accumulation of ara-CTP in leukemic cells remained linear until 1 to 2 h after the infusion. At the time when the rate of ara-CTP accumulation deviated from linearity, the plasma concentration of ara-C was 5- to 20-fold lower [8.1 +/- 4.4 (SD) microM] than the steady-state level during the infusion. Plasma ara-C and cellular ara-CTP pharmacokinetics were studied after two serial infusions in 14 additional patients. Varying the duration of infusion of an ara-C dose between 1, 2, and 4 h (corresponding to infusion rates of 3000, 1500, and 750 mg/m2/h) did not substantially change the rate of ara-CTP accumulation by leukemic cells. The peak ara-CTP concentration and the area under the concentration times time curve (AUC) of ara-CTP in leukemic cells increased with prolongation of the infusion. Although steady-state concentration of ara-C and AUC of ara-C in plasma were proportionally reduced by 1.0 or 0.5 g/m2 infusion over 2 h, ara-CTP accumulation rate and AUC in leukemic cells did not change compared with administration of 3 g/m2 over 2 h. However, when the infusion rate was further reduced to 0.4 or 0.3 g/m2 over 2 h, resulting in steady-state plasma ara-C concentrations of less than 7 microM, the accumulation rate of ara-CTP was substantially reduced as was the ara-CTP intracellular AUC. The cellular elimination rate of ara-CTP remained constant under all infusion conditions. These findings support the conclusion that high-dose ara-C therapy, as currently administered, results in plasma ara-C concentrations that saturate the accumulation of ara-CTP by circulating leukemic cells. We recommend that intermediate dose rates, 200 to 250 mg/m2/h, be evaluated in future studies as an alternative to the substantially higher ara-C dose rates currently in use.
Comparison of the pharmacokinetics of AMSA and AMSA-lactate in patients with acute nonlymphoblastic leukemia.
A pharmacokinetic study was performed in 13 adult patients with acute nonlymphoblastic leukemia to compare two formulations of 4'-(9-acridinylamino)-methanesulphone-m-ansidide (AMSA): the original formulation, AMSA-NCL, and a water-soluble lyophilized formulation, AMSA-lactate (Bristol Myers, Syracuse, N.Y. USA). Initially, the patients received either AMSA-NCL or AMSA-lactate, 75-90 mg/m2 daily, for 3-7 days as a 1-h infusion. Eight patients subsequently crossed over to receive the other formulation. Plasma samples for drug determination were collected during the first 3 days. A new method for determination of AMSA is described. Acidified plasma samples containing an internal standard were extracted with hexane, then made alkaline, whereafter, AMSA was extracted with ethylacetate. Extracts were reconstituted in absolute ethanol and analyzed by high-pressure liquid chromatography (HPLC) using a reverse-phase C-18 column and UV detection at 254 nm. There were no clear differences in clinical effects and toxicity between the two formulations. Patients with the highest total area under the drug concentration-versus-time curves (AUCs) for plasma concentrations versus time had significantly lower nadir for white blood cell count, suggesting a relation between plasma levels and bone marrow toxicity for AMSA. The pharmacokinetics showed a biphasic elimination for both formulations. The mean terminal elimination half-life of AMSA-NCL and AMSA-lactate was 7.1 and 6.3 h, respectively, and the mean volume of distribution was 105 and 99 L/m2, respectively. No significant differences in the pharmacokinetics comparing days 1 and 3 were seen.(ABSTRACT TRUNCATED AT 250 WORDS)
Saturation of ara-CTP accumulation during high-dose ara-C therapy: pharmacologic rationale for intermediate-dose ara-C.
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ara-C in plasma and ara-CTP in leukemic cells after subcutaneous injection and continuous intravenous infusion of ara-C in patients with acute nonlymphoblastic leukemia.
Six patients with acute nonlymphoblastic leukemia (ANLL) were treated sequentially with one subcutaneous (SC) injection (50 mg/m2) and one 156 hour continuous intravenous (IV) infusion (100 mg/m2/d) of 1-beta-D-arabinofuranosylcytosine (ara-C) with an interval of 12 hours. Leukemic cells were isolated from venous blood samples. The intracellular concentration of ara-C 5'-triphosphate (ara-CTP) was determined by high-performance liquid chromatography, and in two of the patients the plasma concentration of ara-C was determined by radioimmunoassay. A rapid biphasic elimination of the drug from plasma with an initial half-life of 18 minutes was seen after SC injection. After about 1.5 hours, the concentration was lower than that obtained at steady-state during continuous IV infusion. In the leukemic cells, the concentration of ara-CTP was higher after SC injection than during continuous IV infusion for about five hours. The mean half-life was 2.1 hours. Judging from the intracellular concentration of ara-CTP, considered to be the active metabolite, the results suggest that SC administration of ara-C can mimic continuous IV infusion if the dose interval is reduced from the traditional 12 hours to four to six hours. The results of this study emphasize the differences between the plasma pharmacokinetics of the parent drug and the concentration of the active metabolite in leukemic cells.
Regulation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate accumulation in human leukemia cells by deoxycytidine 5'-triphosphate.
Cell cycle-specific fluctuations in the ability of human leukemic cells to phosphorylate 1-beta-D-arabinofuranosylcytosine (ara-C) to the toxic metabolite 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) was investigated in whole cells and in cell extracts. Exponentially growing CCRF-CEM cells were fractionated into populations enriched for G1 phase cells and S phase cells by centrifugal elutriation. The accumulation of ara-CTP by S phase-enriched cells was 50% greater than in G1-enriched cells. However, the ability of extracts of S phase-enriched cells to phosphorylate ara-C was twice that of G1 phase-enriched cell extracts. As cells passed from G1 to S phase, this disproportionality was significant. As demonstrated in other cell types, deoxycytidine 5'-triphosphate (dCTP) also potently inhibited ara-C phosphorylation in CCRF-CEM cell extracts (Ki = 5.9 microM). Deoxynucleotide pool levels determined by high pressure liquid chromatography showed a 5 microM dCTP concentration in G1-enriched cells, whereas S phase-enriched cells contained 15 microM dCTP. These findings suggest that the lack of proportionality between the accumulation of ara-CTP in whole cells and the increase of ara-C phosphorylation in extracts during the G1 to S phase transition may be caused by more stringent regulation of ara-C phosphorylation in whole cells by the concomitant increase in cellular dCTP concentrations. Because such regulation is unlikely to be observed in cell extracts, these results indicated that assays of ara-C phosphorylating activity in cell extracts represent upper limits for that function in whole cells. Such determinations may not reflect the regulated nature of the metabolic pathway.
Pharmacokinetics of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in leukemic cells after intravenous and subcutaneous administration of 1-beta-D-arabinofuranosylcytosine.
The concentration of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate was determined in leukemic cells from 5 patients with acute nonlymphoblastic leukemia during treatment with 1-beta-D-arabinofuranosylcytosine (50 mg/sq m every 12 h). The drug was administered both s.c. and i.v. (bolus injection) to all patients. After various periods of time, venous blood samples were collected and leukemic cells were isolated by density gradient centrifugation. The intracellular concentration of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate was assayed by high-performance liquid chromatography. The peak concentration of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate was significantly higher after s.c. injection than after i.v. injection (P less than 0.05). The area under the concentration versus time curve was twice as large after s.c. injection as it was after i.v. injection (P less than 0.01). The results are consistent with clinical findings indicating that the therapeutic effect of 1-beta-D-arabinofuranosylcytosine is better when it is administered s.c. than when given as i.v. bolus injections.
Pharmacologically directed ara-C therapy for refractory leukemia.
During a two-year experience treating patients with refractory acute leukemia with a fixed 12-hour schedule of high-dose ara-C, cellular ara-CTP pharmacodynamics were ascertained in circulating blasts of these patients. A strong correlation was found between achievement of complete remission and cellular ara-CTP levels. We therefore, attempted to improve the complete remission rate in patients with low ara-CTP levels by decreasing the intermittent ara-C dosing interval, thereby raising the minimum ara-CTP level in leukemic cells between doses. This initial attempt at pharmacologic direction of chemotherapy was successful in elevating minimum ara-CTP levels but did not produce an increase in response rate, probably because the total duration of ara-CTP exposure was decreased when the dose intervals were shortened. Currently we are engaged in a new approach based on the knowledge accumulated over the past three years. Patients receive a test ara-C dose from which data on ara-CTP cellular metabolism is derived, followed by a CI of ara-C at a dose calculated individually for each patient. Preliminary results of this approach thus far indicate an increased response rate and a different spectrum of toxicity than that observed with intermittent dose ara-C. Further clinical trials will determine the true effectiveness of this approach.
Relationship of 1-beta-D-arabinofuranosylcytosine in plasma to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate levels in leukemic cells during treatment with high-dose 1-beta-D-arabinofuranosylcytosine.
The pharmacokinetic values of 1-beta-D-arabinofuranosylcytosine (ara-C) in plasma and its active metabolite 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) in circulating blast cells were studied in 11 patients with acute leukemia. ara-C was administered as a 2-h infusion (3 g/m2) followed in 12 to 24 h by a continuous infusion for 4 days in 10 patients and for 7 days in one. A steady-state concentration of ara-C in plasma (94 +/- 32 microM) was reached by the end of the 2-h infusion. Its elimination was biphasic with an initial and terminal t1/2 of 0.44 +/- 0.10 h and 2.8 +/- 0.9 h, respectively. The accumulation of ara-CTP in leukemic cells was linear and continued for up to 2 h after the bolus infusion. ara-CTP elimination was monophasic with a median t1/2 of 3.4 h (range, 1.25 to 18.9 h). The disposition of ara-C and 1-beta-D-arabinofuranosyluracil during continuous infusion was linear with dose rate over the dose range of 70 to 3000 mg/m2/day. The area under the concentration versus time curve for ara-CTP in leukemic cells was not related to the dose infused, but rather appeared to be intrinsic to the cells of each individual. As a general finding, the pharmacokinetic values of ara-CTP in circulating blasts were more heterogeneous than those of ara-C in plasma. There were marked differences in the absolute concentrations of ara-C in plasma and ara-CTP in leukemic cells at different times after the bolus infusion and also during continuous infusion. No correlation was evident between the determinants of ara-C pharmacokinetic values and those of ara-CTP. Thus, it is concluded that the pharmacokinetics of ara-C in plasma cannot predict for the metabolism of ara-CTP in leukemic cells.