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Biomedical subjects

K Lu

Publications and source records attributed to K Lu.

At least 127 records · Page 7Linked to original sources
PubMed1988

Pharmacokinetics of homoharringtonine in dogs.

We studied the pharmacokinetics and distribution of homoharringtonine (HHT), an antitumor alkaloid, in anesthetized dogs using chromatographic and radiochemical techniques. Uniformly tritiated HHT was administered i.v. to five dogs at doses of 0.05 to 0.34 mg/kg, 200 microCi per animal. Unchanged HHT disappeared in a triphasic manner from the plasma with an initial plasma t1/2 of 9.4 +/- 4.2 min, an intermediary t1/2 of 1.4 +/- 0.5 h, and a terminal t1/2 of 40.6 +/- 4.6 h. The plasma clearance was 114.0 +/- 20.1 ml/kg-1 h-1 and the steady-state volume of distribution was 6.2 +/- 0.7 1/kg. In 72 h, 40.1% +/- 4.0% of the administered radioactivity was excreted in the urine, 17.8% +/- 2.7% of which was unchanged HHT. HHT was metabolized extensively to one major and two minor metabolites. Biliary excretion of total radioactivity was 14.4% in 5 h, 2% of which was HHT. HHT concentration in the CSF was highest 4 h after drug administration, about 40% of the concentration in the concurrent plasma. At autopsy 5 h after dosing, the highest percentage of HHT was in the liver (7.4%), followed by the small intestine (2.5%), stomach (1.0%), pancreas (0.8%), kidneys (0.8%), and lungs (0.7%). The heart, spleen, large intestine, and brain each retained less than 0.5%. However, 24 h after dosing, 4% of the HHT still remained in the liver, 1% in the small intestine, and less than 1% in the other organs. HHT seems to be extensively metabolized in dogs and partially retained in the body.

Alkaloids↗
PubMed1987

Central nervous system (CNS) penetration of homoharringtonine (HHT).

Generally tritiated homoharringtonine ([3H]HHT, 150 microCi, 430 micrograms) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [3H]HHT equivalent were determined chromatographically and radiochemically. For [3H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [3H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one.

Alkaloids↗
PubMed1987

Comparison of CNS penetration, tissue distribution, and pharmacology of VP 16-213 by intracarotid and intravenous administration in dogs.

Eight beagle dogs received [3H]VP 16-213 at 2 mg/kg administered intravenously (IV) or intra-arterially (IC) through a catheter inserted into the internal carotid artery. Blood, urine, bile, and cerebrospinal fluid (CSF) samples were collected at intervals. At 1, 6, 24 hr, and 2 weeks after drug administration the dogs were sacrificed and the major organs analyzed for drug concentration. VP 16-213 concentration was determined by radiochemical assay and high pressure liquid chromatography. The plasma t1/2 in the IC group of dogs was 1.0 hr, the volume of distribution was 1.7 L/kg and the clearance was 1.5 ml/hr/kg. In the IV group the values were 1.7, 3.9, and 1.6, respectively. The CSF concentration peaked at 1 hr by both routes, but was higher at all time points in the IC group. At 24 hr and 2 weeks after IC VP 16-213, drug concentration in brain tissue was at least four times higher in the IC group compared with the IV group. In extracranial organs the reverse was true, with the bone marrow cell concentration 1.6 times higher by IV compared to IC (267.2 ng/g and 164.5 ng/g, respectively). Two major and one minor metabolites were found in plasma, urine, bile, and tissue by both routes, however, not all metabolites were found in all organs and body fluids. No acute neurologic toxicity was noted in the IC group and no histopathologic changes by light microscopy were found in the brain or other organs. IC VP 16-213 produced higher drug concentration in the brain of dogs compared with IV administration and was well tolerated at the dosage used.

Animals↗
PubMed1986

Biochemical pharmacology of N-acetyl-N-(methylcarbamoyloxy)-N'-methylurea (caracemide; NSC-253272).

Preclinical pharmacologic studies of caracemide [N-acetyl-N-(methylcarbamoyloxy)-N'-methylurea; CAR] have demonstrated a marked instability of this compound in the presence of either phosphate buffer (pH 7.4) or human plasma. Using [1-14C-acetyl]CAR and [3H-methylcarbamoyloxy]CAR, three CAR degradation products were identified: product A, N-(methylcarbamoyloxy)acetamide; product B: N-(methylcarbamoyloxy)-N'-methylurea; and product C: N-hydroxy-N'-methylurea. CAR degradation in human plasma was demonstrated by high-performance liquid chromatography (HPLC) to occur in a time- and temperature-dependent manner. A 30-min incubation (37 degrees) of CAR (10(-4) M) with human plasma resulted in degradation of more than 55% of parent compound; at 1 hr, more than 75% of original CAR was degraded. Incubation of [1-14C-acetyl]CAR with rat brain homogenate resulted in the formation of 14CO2. This reaction was partially inhibited by coincubation with physostigmine (10(-3) M). CAR inhibited acetylcholinesterase activity in neuroblastoma cells with an IC50 of 14 microM. In mechanism of action studies, CAR was found to inhibit ribonucleotide reductase activity but only at nine times the IC50 of hydroxyurea. In contrast to hydroxyurea, CAR was found to be non-cell-cycle phase-specific and non-cross-resistant with two CHO cell lines resistant to hydroxyurea. These data demonstrate the instability of CAR; moreover, they suggest that its mechanism of cytotoxicity is distinctly different from that of hydroxyurea and that the neurotoxicity associated with CAR administration may be caused in part by inhibition of acetylcholinesterase activity.

Acetylcholinesterase↗
PubMed1986

Clinical pharmacokinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1 H-imidazol-2-yl)hydrazone]dihydrochloride.

We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120-250 mg/m2 IV; one of these patients also received a second dose of 120 mg/m2 6 weeks later, and another received 150 mg/m2 weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t1/2 of 0.6 +/- 0.3 h and a terminal t1/2 of 24.7 +/- 6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1 +/- 5.9 l/kg, and the total clearance was 1045.5 +/- 51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4% +/- 1.1% of dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.

Adult↗
PubMed1986

Clinical pharmacology of intracarotid etoposide.

Pharmacokinetics studies were performed in ten patients who received VP-16 by intracarotid infusion at 100-300 mg/m2. VP-16 was analyzed by high-pressure liquid chromatography. ESTRIP and NONLIN were used to characterize VP-16 pharmacokinetics. VP-16 disappeared biphasically, with a t1/2 beta of 6.1 +/- 1.4 h; the total clearance was 26.8 +/- 2.8 ml/min/m2, and the Vss was 8.8 +/- 1.6 l/m2. The pharmacokinetics was not significantly different after administration by the IV route. However, at a lower dosage, less than 140 mg/m2, the half-life appears to be shorter. This may or may not be significant, since VP-16 pharmacokinetics is quite variable and the number of patients studied is relatively small. Overall, the brain and brain tumor do not appear to have any first-pass effect on VP-16 pharmacokinetics.

Brain↗
PubMed1986

Clinical pharmacology of 4-demethoxydaunorubicin (DMDR).

DMDR, a daunorubicin derivative with a higher therapeutic index and lower cardiotoxicity than either the parent drug or doxorubicin, is active when given PO in experimental animals. We studied its pharmacokinetics in ten patients receiving DMDR IV or PO or IV and PO sequentially at 10-12.5 mg/m2. DMDR and its metabolites were quantified by high-performance liquid chromatography and fluorometry. In nine patients who received DMDR IV the unchanged drug disappeared from the plasma biphasically with a mean terminal half-life of 27.0 +/- 5.5 h, an apparent volume of distribution of 63.9 +/- 12.61 kg-1, and a total clearance of 1.9 +/- 0.41 kg-1 h-1. In 24 h only 5.1% +/- 1.1% of the dose was excreted in the urine. In comparison, in 19 studies the plasma half-life of DMDR given PO was 34.8 +/- 6.7 h, 2.3% +/- 1.3% was excreted in the urine in 24 h, and the maximum plasma drug concentration was reached in about 1 h. The bioavailability of DMDR given PO was about 39% according to comparison of the areas under the plasma DMDR concentration versus time curves for the two routes, but 45% according to comparison of the 24-h cumulative urinary excretion rates. In one patient with severe liver dysfunction following oral administration, the plasma DMDR half-life was 56.8 h, more than twice the average length. By either route, the drug was quickly metabolized to one major metabolite, DMDR-ol. The plasma half-life of DMDR-ol was 72.5 +/- 24.7 h, or 35.7 +/- 7.4 when DMDR was administered IV or PO. In the plasma, DMDR-ol always exceeded DMDR in concentration. Moreover, the 24 h cumulative urinary excretion of DMDR-ol as a percentage of the dose of DMDR administered was 7.8 following IV and 7.4 following PO administration.

Daunorubicin↗
PubMed1986

Clinical pharmacology of homoharringtonine.

Clinical pharmacokinetics of homoharringtonine (HHT) were studied in eight patients who received uniformly labeled HHT at 3-4 mg/m2 (150 mu Ci) by continuous 6-hour infusion. The drug and metabolites were quantified by radiochemical and high-performance liquid chromatographic techniques. Computerized nonlinear least-square regression and curve stripping were used to characterize HHT and total [3H]HHT equivalent pharmacokinetics. Unchanged HHT in the plasma declined biphasically, with an alpha-half-life of 0.5 +/- 0.1 hours and a beta-half-life of 9.3 +/- 1.4 hours. The total clearance of HHT was 177.4 +/- 27.7 ml X hour-1 X kg-1, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4 +/- 0.4 L X kg-1. Correspondingly, the total [3H]HHT equivalent disappeared from the plasma in a triphasic manner. Compared with the pharmacokinetic parameters of unchanged HHT, the terminal half-life of total 3H was 67.5 +/- 7.5 hours, 7.4 times longer; the total clearance was 30.9 +/- 3.1 ml X hour-1 X kg-1, 5.5 times slower; but the volume of distribution by area was 2.7 +/- 0.1 L X kg-1, nearly the same. The 72-hour cumulative urinary excretion of total tritium was 28.2% of the administered dose and only 38.3% of this resided in unchanged HHT. Thus, urinary excretion was not a major route of elimination of HHT. Moreover, HHT underwent extensive metabolism; one major and two minor unidentified products were detected in both plasma and urine.

Adolescent↗
PubMed1984

Central nervous system pharmacology of Baker's antifolate (NSC139105) in man.

Radiolabelled Baker's Antifolate (BAF) was administered to 6 patients undergoing surgical resection of intracerebral tumors. Levels of radioactivity in resected tumor and edematous brain adjacent to tumor were generally higher than levels in concurrent plasma samples and were generally comparable to levels in temporalis muscle. Levels in tumor cyst fluid were far lower than concurrent plasma levels and levels in surrounding tumor. Chromatography was performed on tumor from 2 patients and revealed that only a small proportion of the radioactivity represented unchanged BAF. The major metabolite present in tissues was 1 000 times less potent as an inhibitor of dihydrofolate reductase than was BAF. Five patients had cerebrospinal fluid (CSF) sampled following administration of tracer doses of radiolabelled BAF. Radioactivity levels were far lower in CSF than in plasma. Levels of radioactivity in the CSF were also far lower than levels in tumor and brain samples from other patients and were slightly lower than tumor cyst fluid levels. Two patients had CSF collected after they received therapeutic doses of BAF. In these patients, both CSF and plasma were assayed using a dihydrofolate reductase inhibition assay. As with tracer dose studies, CSF concentrations of BAF were substantially lower than were concurrent plasma concentrations. Thus it appears that only very low concentrations of BAF are attainable in human CSF and intracerebral tumor, although a metabolite which is a very weak inhibitor of dihydrofolate reductase attains high concentrations in tumor.

Antineoplastic Agents↗
PubMed1984

Human tissue distribution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (NSC 141549, AMSA).

Concentrations of AMSA were determined by HPLC in autopsy tissue samples from five patients who had received the drug antemortem. Relative organ concentrations of AMSA varied from patient to patient; however, concentrations were generally highest in gallbladder, liver, and kidney, while low levels were generally but not invariably found in lung, testicle, muscle, fat, spleen, bladder, pancreas, colon, prostate, and brain. One patient with ventricular fibrillation and seizures had high tissue AMSA concentrations in myocardium, but low concentrations in brain. Another patient with seizures during treatment had high brain concentrations of AMSA. Relative organ concentrations were similar to those found in mice, except that mice have high AMSA concentration in their spleens whereas our patients did not, even when the spleen was infiltrated with leukemic cells. High tissue concentrations of AMSA were still present 2 weeks after treatment. AMSA concentration was lower in a renal oncocytoma (1.1 micrograms/g) than in surrounding kidney (2.4 micrograms/g).

Adult↗
PubMed1984

Pharmacological disposition of 1,4-dihydroxy-5-8-bis[[2 [(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride in the dog.

DHAQ, a new antitumor agent, has been selected for clinical trial on the basis of its activity against a number of transplantable rodent tumors. In anticipation of the clinical trial of this agent, the pharmacology of DHAQ was studied in beagles by high-pressure liquid chromatographic and radiochemical techniques that are specific for the unchanged drug. 14C-DHAQ was administered IV to beagles at a dose of 5 mg/kg, 100-125 microCi total. With a maximal plasma concentration of 75 +/- 2.7 ng/ml, DHAQ was eliminated from the plasma with a half-life of 28.1 h during the terminal phase. The total clearance of DHAQ was 10.1 +/- 0.4 mg/kg/min, while the apparent volume of distribution was 26.6 +/- 4.9 l/kg. In 48 h, 2.4% +/- 0.6% of the dose was excreted in the urine and 3.0% +/- 0.1% in the bile as the unchanged drug. At autopsy performed 5 h after dosing, the highest percentage of the administered DHAQ was in the liver (49.7% +/- 2.7%), followed by the small intestine (7.1% +/- 0.7%), kidneys (2.7% +/- 0.1%), lung (1.9% +/- 0.3%), spleen (1.6% +/- 0.3%), and stomach (1.3% +/- 0.1%). The heart, large intestine, pancreas, gallbladder, urinary bladder, and brain each retained less than 1% of the dose. However, 24 h after dosing 10.6% of the drug was detected in the liver and 2.9% in the small intestine. In terms of the percentage of the dose, the distribution of DHAQ in the other organs either remained unchanged or increased slightly. In concentrations varying from 10 ng/ml to 10 micrograms/ml the drug was 70%-80% bound to plasma protein. DHAQ was metabolized to two unidentified metabolites. Thus, this drug appeared to be cleared from the plasma of beagle dogs chiefly by tissue binding, leading to possible persistence of the drug in certain body compartments.

Animals↗
PubMed1984

Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule.

A Phase I trial of tricyclic nucleoside phosphate (1,4,5,6,8-pentaazaacenaphthylene-3-amino-1, 5-dihydro-5-methyl-1-beta-D-ribofuranosyl 5'-phosphate ester; NSC 280594) was conducted using a 5-day continuous infusion schedule. Thirty-seven patients with advanced cancer were entered on the study, of whom 33 patients were evaluable for response and toxicity. Dose levels ranged from 10 mg/sq m/day X 5 days to 40 mg/sq m/day X 5 days. Initially, courses were repeated every 3 to 4 weeks. As cumulative toxicity became manifested, the interval between courses was changed to every 6 weeks. Major toxicities included hyperglycemia, hepatotoxicity, and thrombocytopenia. Patients with a prior history of diabetes mellitus, extensive radiation therapy, or significant liver metastases were prone to severe toxicity. Other toxicities noted were nausea and vomiting, abdominal discomfort, anemia, and reduction in serum calcium, phosphorus, and albumin levels. Rare side effects included hypertriglyceridemia, hyperamylasemia, diarrhea, and stomatitis. Antitumor activity observed include improvement in s.c. metastases in a patient with papillary thyroid carcinoma, stabilization of disease in a patient with mesothelioma, and mixed responses in three patients (colon cancer, sarcoma, and tonsillar squamous cell cancer). Recommended schedule for Phase II studies is 20 mg/sq m/day for 5 days every 6 weeks.

Acenaphthenes↗
PubMed1983

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986).

[14C]AZQ (2-4 mg/m2, 100-200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18-45% of the total radioactivity in tumor tissue and 30-56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/g vs. 31 ng/g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

Adult↗
PubMed1983

The pharmacologic fate of 2,5-diaziridinyl-3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ NSC-182986) by intracarotid or intravenous administration in beagles.

Beagle dogs received either intravenous (I.V.) or intracarotid (I.C.) 14C ring labelled 2,5-diaziridinyl-3,6-bis-(carboethoxyamino) 1,4-benzoquinone (AZQ) at a dose of 2 mg/kg. Blood, urine and cerebrospinal fluid (CSF) samples were collected at intervals. At varying times, dogs from each group were sacrificed and histologic examination and drug determinations were performed on the major organs. By both routes of administration, the elimination of AZQ from plasma was biphasic with an initial half-life of 18 min and a terminal half-life of 26 hr. The apparent volume of distribution was 7.9 l/kg and the total clearance was 3.5 ml/kg/h. The 96 hr cumulative urinary excretion of total 14C was 41% of the administered dose, including 4% as the unchanged drug. At 1, 48, and 96 hr after I.C. AZQ, drug concentrations in the brain tissue were twice those by the I.V. route. High drug concentrations in the CSF were produced by both routes, although the CSF to plasma ratio was higher by I.C. than I.V. In extracranial organs, tissue concentrations of AZQ were at least twice as high by I.V. than by I.C. administration. No significant clinical or neurologic toxicity were noted when AZQ was given I.C. In the dog I.C. administration of AZQ seems to accelerate drug entry into the brain tissue.

Animals↗
PubMed1983

Concentration of vinblastine in human intracerebral tumor and other tissues.

Uptake of vinblastine into human cerebrospinal fluid, intracerebral tumor and autopsy tissues was quantitated radiochemically after separating vinblastine from its metabolites by high pressure liquid chromatography. Only low concentrations of vinblastine were found in cerebrospinal fluid from a single patient. A second patient who received a tracer dose of radiolabelled vinblastine prior to surgical resection of an intracerebral tumor had slightly less radioactivity in tumor than in temporalis muscle, but more in tumor than in edematous brain surrounding the tumor. The radioactivity in tumor increased gradually and exceeded concurrent plasma radioactivity by 2 hr after drug administration. A third patient died 4 hr into a planned 24-hr infusion of radiolabeled vinblastine. Highest vinblastine concentrations were found in organs with high blood flow such as kidney and heart. Intermediate concentrations were found in liver and lung, and low concentrations were found in prostate, gastrointestinal tract, spleen, muscle, bladder, and hepatic and lymph node metastases. A fourth patient died one month after receiving radiolabeled vinblastine. Highest concentrations were in liver and next highest concentrations were in intracerebral tumor. Moderately high concentrations were found in pancreas, thyroid, lung, spleen, ovary, kidney, and kidney metastases. Lowest concentrations were found in omental metastases, heart, breast, and brain. Vinblastine concentration decreased with increasing distance into brain from the brain metastases. Thus, vinblastine was not selectively localized in tumors. The concentrations in tumor did not reflect the concentration in the organ in which the tumor was located. There was no indication that uptake into intracerebral tumor was impaired. Cerebrospinal fluid and brain concentrations of vinblastine did not give any indication of the concentration attainable in intracerebral tumor.

Adult↗
PubMed1983

Clinical pharmacology of 2,5'-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ).

2,5'-Diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ) is an alkylating compound which has exhibited a broad spectrum of antitumor activity against a variety of experimental tumors, particularly those implanted intracranially. We have studied the clinical pharmacology of AZQ in 11 patients with various types of tumors. AZQ was administered at 1-12 mg/m2 daily for 5 days by i.v. infusion in 10-30 min. 14C-labelled AZQ was given on day 1 only. Blood and urine specimens were analyzed radiochemically and chromatographically. The plasma disappearance of unchanged AZQ was essentially biphasic, with an initial plasma t 1/2 of 1.4 +/- 0.4 hr and a terminal t 1/2 of 45.5 +/- 3.1 hr. The apparent volume of distribution was 14.2 +/- 3.0 l/kg. The cumulative urinary excretion of unchanged AZQ was 4.3% in 24 hr and 8.6% in 96 hr. The total clearance of the drug was 200 ml/kg/hr. Cerebrospinal fluid AZQ concentration peaked 45-90 min after drug administration, reaching about 70% of that in plasma, and then declined at nearly the same rate.

Antineoplastic Agents↗
PubMed1983

Tumor penetration of AMSA in man.

4'-(9-Acridinylamino)-methanesulfon-m-anisidide (AMSA) has shown significant antitumor activity against several murine tumors and leukemias. During its Phase I and II clinical trial, we were able to obtain tumors, plasma, and CSF specimens from patients who received varying doses of AMSA, as well as patients who received high doses and had autologous bone marrow rescue. The drug was analyzed chromatographically. The tumor to plasma drug concentration ratios ranged from 200% to 486%, apparently independent of dose and sampling time. Because AMSA was not detected in the CSF, the drug may not be effective in the treatment of meningeal metastasis. High-dose AMSA therapy with bone marrow rescue did not result in significantly higher AMSA concentrations in the tumor, nor did it elicit favorable response.

Aged↗