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Biomedical subjects

R L Furner

Publications and source records attributed to R L Furner.

8 recordsLinked to original sources
PubMed1979

Kinetics of intravenous melphalan.

We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High-pressure liquid chromatography and 14C-melphalan were used to assay drug concentration in plasma and urine. Composite plasma t1/2alpha was 7.7 +/- 3.3 and t1/2beta was 108 +/- 20.8 min for 8 of the patients. The mean 24-hr urinary excretion of melphalan was 13.0 +/- 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured 14C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein-bound activity). These data and evidence of rapid disappearance from plasma at 37 degrees in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t1/2 of melphalan in vivo.

Adult↗
PubMed1977

Pharmacokinetics of the absorption, distribution, and elimination of melphalan in the dog.

[14C]melphalan ([14C]L-PAM) was rapidly absorbed from the gut of dogs after oral dosing and reached a maximum concentration in the serum by 30 minutes. The disappearance of L-PAM (intact drug) from the serum was biphasic after iv administration, with half-lives of 14 and 66 minutes for the alpha and beta phases, respectively. The urinary excretion accounted for 44% of the total radioactivity and 25% appeared in the feces. Approximately 8% of the dose was excreted unchanged in the urine. Biliary excretion was rapid, with 11% of the dose being accounted for in the bile after 30 minutes; approximately 80% of these drug equivalents (materials containing radioactivity) was parent compound. Since large amounts of L-PAM appeared in the bile, the agent may prove to be active against cancers of the gall bladder, bile ducts, and duodenum.

Animals↗
PubMed1975

Influence of tetrahydrouridine on the phosphorylation of 1-beta-D-arabinofuranosyl-cytosine (ara-C) by enzymes from solid tumors in vitro.

The phosphorylation of 1-beta-D-arabinofuranosylcytosine (ara-C) was studied in cell-free extracts from a variety of solid mouse tumors, L1210 ascites and in normal liver and spleen. Two apparent Michaelis constants were observed for kinase activity in Lewis lung (Km1, 4.15 muM; Km2 58.1 muM), sarcoma 180 (Km1 6.66 muM; Km2 56.18 muM), adenocarcinoma 755 (Km1 4.34 muM; Km2 50.0 muM) and l1210 (Km1 29.41 muM; Km2 41.67 muM). The Km1 values generally ranged from 5 to 20 muM 3H-ara-C while the Km2 values ranged from 20 to 60 muM 3H-ara-C. Normal spleen (Km 47.6 muM), normal liver (Km 10.0 muM) and Ridgway osteogenic sarcoma (Km 31.2 muM) had single Km values. In the presence of tetrahydrouridine (H4U), the in vitro phosphorylation of ara-C was increased as much as 91% in cell-free extracts from adenocarcinoma 755; lesser increases were observed in other tumor extracts. At low substrate concentrations, the apparent Km decreased or did not change in the presence of H4U, while at higher substrate concentrations the apparent Km was increased or did not change in the presence of H4U. In the presence of H4U, Vmax for kinase activity increased most in those tumors possessing deaminase activity.

Adenocarcinoma↗
PubMed1975

Kinase and deaminase activity in a variety of subcutaneous mouse tumors.

Extracts of solid mouse tumors were examined for deoxycytidine kinase and deaminase activities. 1beta-D-Arabinofuranosylcytosine nucleotide was formed at a rate of 45 nmoles/hr by Glioma 26/57 and only 14 nmoles/hr by Ridgway osteogenic sarcoma. Deaminase activity was highest in Lewis lung (114 nmoles of 1-Beta-D-arabinofurano-syluridine formed per hr) and in CaD2 (104 nmoles of u-beta-D-arabinofuranosyluridine formed per hr). Deaminase activity in tumor extracts is sensitive to freezing, while deaminase activity in monkey serum is not. It was observed that kinase activity varies by as much as 50% in different cell lines of the same tumor. In the presence of tetrahydrouridine, kinase activity was significantly increased in most of the tumors studied.

Adenocarcinoma↗
PubMedDate not supplied

A method for the measurement of L-phenylalanine mustard in the mouse and dog by high-pressure liquid chromatography.

The distribution of L-phenylalanine mustard (L-PAM) was studied in dogs and mice by high-pressure liquid chromatography. Separation of L-PAM from its products of hydrolysis was accomplished with a mu-Bondapak C18 column, a solvent system composed of 2-methoxyethanol/0.1% acetic acid, and solvent programming with a step gradient. Complete separation was effected in less than 15 min. The half-life for disappearance of L-PAM from mouse blood was 41 min, whereas that from dog blood was 29 min. The monohydroxy derivative of L-PAM, L-MOH, disappeared from dog serum with a half-life of 32 min. L-MOH was not detectable in mouse tissue other than blood at times greater than 15 min after injection. In the dog at 4 hr after injection, the tissue/serum concentration ratios were greater than 1 for liver, spleen, intestine, skeletal muscle, urinary bladder and gallbladder. The concentration of L-PAM in the bile was approximately 500 times higher than that in serum.

Animals↗
PubMedDate not supplied

Pharmokinetics of 2'-deoxycoformycin in normal and L1210 leukemic mice.

Following intravenous administration, 2'-deoxycoformycin (0.25 mg/kg) was rapidly distributed to tissues of both normal mice and mice bearing L1210 leukemia cells and readily eliminated, primarily by urinary excretion. Elimination of 2'-deoxycoformycin from plasma was biphasic, and half-lives for the alpha- and beta-phases of 10 and 33 min for normal mice and 7 and 40 min for L1210-bearing animals. The volume of distribution at steady state was approximately 20 ml, suggesting that the drug was distributed in the total body water for both groups of mice. The kidney, liver, small intestine, spleen, thymus, and L1210 tumor had tissue/plasma ratios greater than or equal to 1 at 15 min after dosing. In both groups, greater than 90% of the dose of 2'-deoxycoformycin was recovered in the urine within 3 hr. As determined by bioautography of urine samples, no detectable metabolism occurred. The presence of the L1210 tumor caused changes in the tissue distribution of 2'-deoxycoformycin. At later time periods, tissues from tumor-bearing mice contained significantly higher levels of this drug when compared to normal mice. However, the tumor was without significant effect on blood levels or urinary excretion of 2'-deoxycoformycin.

Animals↗
PubMedDate not supplied

Inhibition of deamination of 14C-cytosine arabinoside (NSC-63878): a useful biologic assay for tetrahydrouridine (NSC-112907).

Inhibition of the deamination of 14C-cytosine arabinoside by two lots of tetrahydrouridine was studied in monkey serum. The average inhibition of deaminase activity was 78% for tetrahydrouridine lot AJ39 (1.0 muM) when the concentration of cytosine arabinoside ranged from 44.2 to 170.7 muM; under the same conditions tetrahydrouridine lot AJ22 inhibited deamination by an average of 68%. Apparent Ki values were 0.26 muM for AJ39 and 0.43 muM for AJ22. The assay may be used to check the relative biologic activity of various lots of tetrahydrouridine.

Animals↗