Clinical pharmacology of 4-demethoxydaunorubicin (DMDR)

Summary 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.This study was supported by ADRIA Laboratory     

Clinical pharmacokinetics of 3-deazaguanine

Summary 3-Deazaguanine (3DG), an antipurine antimetabolite, has recently completed a phase I clinical trial at this Institute. The drug was given on a dailyx5 schedule by i.v. infusion over 0.25–2.16 h. The pharmacokinetics of 3DG during 16 courses were studied in 12 patients at doses of 200–800 mg/m². 3DG in plasma was measured by an isocratic reverse-phase high-performance liquid chromatographic (HPLC) procedure carried out on IBM phenyl columns at 40° C using 10mM phosphate buffer (pH 7) as the mobile phase and detection at 300 nm. Plasma decay of 3DG was biexponential in all patients. The AUC correlated linearly with dose at 200–600 mg/m² but deviated from linearity at doses>600 mg/m². The drug was cleared rapidly from plasma; at doses of 200–600 mg/m², the mean plasma clearance was 61.64±9.97 l/h and the mean terminal-phase elimination half-life was 1.6±0.6 h. The steady-state volume of distribution (98.8±29.1 l) and distribution coefficient (1.24±0.39 l/kg) indicated extensive tissue distribution for the drug. No statistically significant difference was observed between the pharmacokinetics of 3DG on day 1 and that on day 4 as evaluated in three patients for whom complete plasma data were available on both days.     

Pharmacokinetics of 7-con-O-methylnogarol in patients with solid tumors

Summary The pharmacokinetics of 7-con-O-methylnogarol were investigated by HPLC assay with fluorometric detection in nine cancer patients with normal hepatic and renal function, after a 2-h infusion of 160 or 200 mg/m². The drug disappeared from plasma biexponentially with a mean elimination half-life of 38±3 h; the mean apparent volume of distribution and the plasma clearance were 805±91 l/m² and 14±2 l/h per m². Within 48 h of administration, urinary excretion of the drug and its metabolite 7-con-O-methyl-N-demethylnogarol accounted for 2%–15% and 0.1%–6% of the dose, respectively. Neither 7-con-O-methylnogarol nor its N-demethyl derivative was conjugated with glucuronic acid or sulfate in detectable amounts.     

Pharmacokinetics of unchanged carboplatin (CBDCA) in patients with small cell lung carcinoma

Summary The disposition of the cisplatin analogue carboplatin was studied in seven patients with small cell lung cancer. Carboplatin 100 mg/m² was administered without hydration by a 1-h infusion with VP16-213 120 mg/m² on days 1, 2 and 3 of each course. Plasma and urine collections were made on days 1 and 3 of the first course of treatment. Carboplatin levels in plasma ultrafiltrate and urine were quantitated using a specific and sensitive, highperformance liquid chromatographic assay which involved sample clean-up on a Dowex-2 column prior to injection. Estimates of pharmacokinetic parameters determined using either compartmental or non-compartmental methods were comparable. There was no difference between carboplatin pharmacolinetic parameters determined on days 1 and 3 of treatment. The mean (±SD) carboplatin half-life determined from plasma data on day 1 was 105±30.4 min and was not significantly different from that determined using urinary excretion rate data (107±51.7 min). Urinary excretion rate plots showed that carboplatin elimination was mono-exponential for up to 14 h after infusion. Totalbody clearance was 105±40.0 ml min^-1 m^-2, renal clearance 64.3±44.1 ml min^-1 m^-2, and volume of distribution 17.3±4.2 l/m² on the 1st day of treatment. Of the administered dose, 58.4%±21.2% was recovered in urine over a 24-h period after the start of the infusion. The mean renal clearance of carboplatin was comparable to creatinine clearance. Carboplatin disposition was clearly defined in the patients studied using analytical methodology specific for the unchanged drug.     

Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

Pharmacokinetics of 10-ethyl-10-deaza-aminopterin,edatrexate, given weekly for non-small-cell lung cancer

Summary We studied the pharmacokinetics of 10-ethyl-10-deaza-aminopterin (10-EdAM), edatrexate and its 7-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m² was given weekly, with dose reduction being undertaken for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was seen, the mean half-lives being 0.10±0.07, 0.8±0.3 and 7±7 h, respectively. The mean plasma clearance was 25±14 l/h, with 18%±11% of the dose appearing unchanged in the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) withr ²=0.976. There was considerable variation of the clearance both within and between patients but there was no evidence of a dependence on time or dose. The 1-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was shown to be related to both the AUC of the drug and that of its 7-OH metabolite.This work was supported by a grant from Ciba-Geigy Ltd.     

Bleomycin clinical pharmacology by radioimmunoassay

Summary Bleomycin pharmacokinetics were studied by radioimmunoassay in 11 patients who received 7–30 U intravenously (IV) and eight patients who received 4–30 U subcutaneously (SC). For patients who received IV bleomycin plasma disappearance was biphasic, with a mean initial half-life of 0.26 h and a terminal half-life of 2.3 h. Mean plasma drug clearance was 67.8 ml/min/m² and the volume of distribution was 13.2 l/m². Urinary excretion accounted for 63.9% of the drug in 24 h. After SC administration peak plasma levels occurred in 1.1 h, with a mean elimination half-life of 4.3 h. Mean plasma drug clearance was 60.5 ml/min/m² and the volume of distribution was 19.2 l/m². Bleomycin plasma clearance correlated well with serum creatinine (r²=0.72).Bleomycin has a rapid plasma elimination and urinary excretion. Bleomycin bioavailability after SC administration appears comparable to that seen after IV administration as determined by the areas under the plasma disappearance curves. Prolonged plasma levels are seen after SC injection, suggesting this route of administration can produce plasma concentrations comparable to those attained with continuous IV infusions.     

Single and repeated dose pharmacokinetics of thio-TEPA in patients treated for ovarian carcinoma

Summary Triethylenethiophosphoramide (thio-TEPA) pharmacokinetics were studied in 15 patients being treated for epithelial ovarian carcinoma. Unchanged thio-TEPA was assayed in serum and urine by means of a gas chromatographic procedure.No accumulation or alteration of the pharmacokinetics occurred during therapy, which was continued for up to 7 months with biweekly administrations of 20 mg, after two initial loading courses with 20 mg daily for 3 consecutive days 2 weeks apart. No significant difference in the pharmacokinetics between i. m. and i. v. administration was demonstrated. However, three patients showed a reduced absorption ability from the i. m. injection site to the systemic circulation and an apparent increase in the elemination half-life (3.86±0.97 h), which could be of clinical relevance.A first-order elimination process with a short elimination half-life (1.5 h) was demonstrated for thio-TEPA in all patients after i.v. administration. The apparent volume of distribution averaged 50 1. The renal clearance was below 1% of the total-body clearance, which averaged 412 ml/min. The urinary excretion of unchanged thio-TEPA was complete within 8 h after administration, with an average urinary recovery of 0.14% of the dose. Calculation of the area under the serum concentration vs time curve revealed wide variation between patients (range 517–1480 ng/h ml^-1), indicating the need for drug monitoring during therapy.The work described in this paper was supported by grants from The Norwegian Cancer Society (Oslo) and the Regional Hospital (Trondheim)     

Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I–II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III–IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2×300 to 2×500 mg/m². Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination halflives of 4.15±2.57 and 28.8±12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96±2.89 to 12.22±3.95 mg l^–1h. Drug clearance was independent of the dose given and equal to 109±65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r=0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.     

The kinetics of the auto-induction of ifosfamide metabolism during continuous infusion

It has often been reported that the oxazaphosphorines ifosfamide and cyclophosphamide induce their own metabolism. This phenomenon was studied in 21 paediatric patients over 35 courses of therapy. All patients received 9 g m^–2 of ifosfamide as a continuous infusion over 72 h. Plasma concentrations of parent drug and of the major metabolite in plasma, 3-dechloroethylifosfamide (3DC) were determined using a quantitative thin-layer chromatography (TLC) technique: A one-compartment model was fitted simultaneously to both ifosfamide and 3DC data. The model included a time-dependent clearance term, increasing asymptotically from an initial value to a final induced clearance and characterised by a first-order rate constant. A time lag, before induction of clearance began, was determined empirically. Metabolite kinetics were characterised by an elimination rate constant for the metabolite and a composite parameter comprising a formation clearance, proportional to the time-dependent clearance of parent drug, divided by the volume of distribution of the metabolite. Thus, the parameters to estimate were the volume of distribution of parent drug (V), initial clearance (Cli), final clearance (Cls), the rate constant for changing clearance (Kc), the elimination rate constant for the metabolite (Km) and Vm/fm, the metabolite volume of distribution divided by the fractional clearance to 3DC. The model of drug and metabolite kinetics produced a good fit to the data in 22 of 31 courses. In a further 4 courses an auto-inductive model for parent drug alone could be used. In the remaining courses, auto-induction could be demonstrated, but there were insufficient data to fit the model. For some patients this was due to a long time lag (up to 54 h) relative to the infusion time. The time lag varied from 6 to 54 (median, 12) h and values for the other parameters were Cli, 3.27±2.52 l h^–1m^–2, Cls, 7.50±3.03 l h^–1m^–2, V, 22.0±11.0 l m^–2,Kc, 0.086±0.074 h^–1;Km, 0.159±0.077 h^–1 and Vm/fm, 104±82 l m^–2. The values ofKc correspond to a halflife of change in clearance ranging from 2 to 157 h, although for the majority of the patients the half-life was less than 7 h and a new steady-state level was achieved during the 72 h infusion period. This model provides insight into the time course of enzyme induction during ifosfamide administration, which may continue for up to 10 days in some protocols. Since other drugs, including common anti-neoplastic agents, are metabolised by the same P450 enzyme as is ifosfamide, auto-induction may have implications for the scheduling of combined chemotherapy.     

Disposition of total and free cisplatin on two consecutive treatment cycles in patients with ovarian cancer

Summary The disposition of total and ultrafilterable cisplatin was determined in 12 women with ovarian carcinoma receiving cyclophosphamide 500 mg/m², adriamycin 50 mg/m² and cisplatin 50 mg/m² during their first and second course. Plasma samples were obtained over 96 h following the completion of the cisplatin infusion and assayed for total platinum by atomic absorption spectroscopy. Plasma samples obtained up to 4 h after cisplatin infusion contained measurable ultrafilterable (free) cisplatin. The mean disposition of free cisplatin conformed to a two-compartment model with a mean terminal half-life (±SD) of 46.2±20.2 min during the first course and 37.8±18.0 min during the second course of therapy.The mean disposition of total cisplatin conformed to a three-compartment model with a mean terminal half-life (±SD) of 57.8±19.3 h during the first course and 86.6±33.3 h during the second course of therapy. We found that the mean total cisplatin levels were significantly higher during the second course than the first course and the total body clearance of total platinum decreased from the first to the second course. Divided urine collections were obtained over 24 h after completion of cisplatin infusion, but cisplatin was not always detectable at all time intervals. The total fraction recovered was 0.14 and 0.12 of administered dose after the first and the second course, respectively. Renal clearance was 0.61±0.32 l/h/m² and 0.45±0.16 l/h/m² for the first and the second course, respectively.We conclude that: (1) urinary platinum excretion is variable between patients and with time; (2) a trend to decreased renal clearance of platinum from first to second course may be due to a decrease in renal excretion of cisplatin; and (3) the body's elimination pathways clear less platinum upon repeat administration.Supported in part by a grant from Adria Laboratories, Columbus, Ohio     

Pharmacokinetic study of fludarabine phosphate (NSC 312887)

Summary Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m² daily x5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentrationtime curves yielded an average distribution half-life (t1/2) of 0.60 h and a terminal half-life (t1/2) of 9.3 h. The estimated plasma clearance was 9.07±3.77 l/h per m² and the steady state volume of distribution, 96.2±26.0 l/m². There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r=-0.94, P<0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r=0.828; P<0.1). Aproximately 24%±3% of 2-FLAA was excreted renally over the 5-day course of drug administration.Abbreviations used 2-FLAA-9--D arabinofuranosyl-2-fluoroadenine - 2-FLAMP the 5'-monophosphate of 2-FLAA, also known as fludarabine phosphate - AUC area under the curve - AGC absolute granulocyte count - TPC total plasma clearance - Vd_ss volume of distribution at steady state - Vd volume of distribution - Creat Cl creatinine clearance - SGOT serum glutamic-oxaloacetic transaminase - WBC peripheral white blood cell count This study was supported by contract NCI N01-CM-27542, NIH grant RR-01346 and by the VA Research Service.     

The effects of cimetidine upon the plasma pharmacokinetics of doxorubicin in rabbits

Summary Cimetidine is an H₂ antagonist which inhibits cytochrome P-450 and reduces hepatic blood flow. To determine whether cimetidine interferes with the plasma pharmacokinetics of doxorubicin, we gave six female New Zealand rabbits doxorubicin 3 mg/kg, followed a month later by cimetidine 120 mg/kg every 12 h over 72 h and doxorubicin 3 mg/kg. Serial plasma specimens were obtained over 72 h and assayed for doxorubicin and its metabolites by high-performance liquid chromatography and fluorescence detection.Doxorubicin plasma pharmacokinetics were prolonged after cimetidine pretreatment [AUC 0.76±0.22 vs. 2.85±1.22 M×h, no pretreatment vs pretreatment (p=0.005), half-life=11.7±6.55 vs 28.0±8.16 h (P=0.0002), and clearance=0.129±0.036 vs 0.036±0.0111/min^-1 kg^-1 (P=0.0007)]. No significant differences were found between the AUCs for doxorubicinol, 7-deoxy doxorubicinol aglycone, or two unidentified nonpolar metabolites in nonpretreatment and pretreatment studies. Cimetidine increases and prolongs the plasma exposure to doxorubicin in rabbits. Doxorubicin metabolism does not appear to be affected by cimetidine.Grant Support Veterans Administration, NIH Grant RR-05424 and Clinical Research Center Grant RR-00095 American Cancer Society Institutional Grants #IN25V and IN24V, and JFCF #649     

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

Summary 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 t_1/2 of 0.6±0.3 h and a terminal t_1/2 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 the 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 t_1/2 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.     

Phase I and pharmacokinetic studies with the pentacyclic pyrroloquinone mitoquidone

Summary Mitoquidone (MTQ) is the first member of a new group of pentacyclic pyrroloquinones developed for clinical evaluation as a potential anticancer agent. MTQ demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. Twenty-seven patients were treated with MTQ given as a 4-h infusion either once every 21 days (150–600 mg/m²), once a week (200 mg/m² per week), or as 5 daily doses repeated every 28 days (60–180 mg/m² per day). The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies. Temporary remission of B-symptoms occurred in two patients with lymphoma. The plasma pharmacokinetics of MTQ were investigated using an HPLC assay with fluorescence detection. Linear pharmacokinetics were observed with a terminal plasma half-life of 2.9±2.1 h (n=18 doses). The volume of distribution was 3.4±2.6 l/kg and plasma clearance was 629±469 ml/min per m². Several soluble analogues with similar antitumour activity are currently under investigation.This work was supported by Glaxo Group Research Ltd., Greenford, UK     

Pharmacokinetics of ametantrone acetate (NSC-287513)

Summary Ametantrone is the second anthracene derivative to enter clinical trials. The pharmacokinetic parameters for ametantrone acetate (CI-881) were characterized in six patients concurrently with the phase I clinical trial. Biological samples were assayed by a specific and sensitive high-performance liquid chromatography procedure. Plasma levels of ametantrone declined in a triexponential fashion, with a mean terminal half-life (t_1/2 gamma) of 25 h. The estimated mean total-body plasma clearance was 25.9±14.7 l h^-1 m^-2. The steady-state volume of distribution (Vdss) was large, averaging 568±630 l/m². Excretion of unchanged ametantrone in the urine over 48 h averaged 5.7% of the total dose, indicating that there is another major route of elimination.This study was supported by a grant from Warner-Lambert/Parke-Davis Company, Pharmaceutical Research Division, Ann Arbor, Michigan 48105, and the General Clinical Research Center, NIH, DHHS (Grant RR-01346), and the clinical and support services of Audie L. Murphy Memorial Veterans Hospital, San Antonio, Texas     

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit

Summary Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enchanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low- protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8–12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1,n=15; group 2,n=14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48±3 vs 59±4 ml min^–1 kg^–1;P<0.05), prolonged the terminal climination half-life (28±2 vs 22±2 h;P<0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722±122 vs 1405±71 ng h ml^–1;P<0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-portein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52±5 vs 40±2 h;P<0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.Supported by the Department of Veterans Affairs and the American Heart Foundation     

Pharmacokinetics of acridine-4-carboxamide in the rat,with extrapolation to humans

Summary The pharmacokinetics ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) were investigated in rats after i. v. administration of 18, 55 and 81 mol/kg [³H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (±SD) model-independent pharmacokinetic parameters were; clearance (Cl), 5.3±1.1 1 h^–1 kg^–1; steady-state volume of distribution (Vss), 7.8±3.0 l/kg; mean residence time (MRT), 1.5±0.4 h; and terminal elimination half-life (t _1/2Z), 2.1±0.7 h (n=10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1–8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05–0.10; 95% confidence limits) 1 h^–1 kg^–1 and a V_ss value of 0.63 (range, 0.2–1.1) l/kg for total drug concentrations in humans.     

Uridine pharmacokinetics in cancer patients

Summary The availability of uridine can alter the sensitivity of tumor cells to antimetabolites such as N-phosphonacetyl-l-aspartic acid (PALA) and acivicin by virtue of the cell's ability to salvage preformed metabolites from its environment. We investigated the pharmacokinetics of physiologically relevant amounts of uridine in cancer patients in a pilot study to further our understanding of uridine metabolism in the human body. Four cancer patients, two males and two females, were given an i.v. bolus of a trace amount of radiolabeled uridine. The nucleoside disappeared from the plasma in a triphasic manner, with initial half-lives of 0.57±0.28 and 1.79±0.62 min and a terminal half-life of 17.5±7.3 min. The volume of distribution was 481±70 ml/kg, and the plasma uridine clearance was calculated to be 1.70±0.42 l/min. Simultaneous plasma and bone marrow uridine concentrations were measured in a separate group of seven healthy volunteers. The uridine concentration in plasma was 2.32±0.58 M, and that in the bone marrow plasma was 10.44±5.06 M. These results suggest a very rapid turnover of uridine in the plasma when the nucleoside is present at physiologic concentrations, and that there is a locally high concentration of uridine available for salvage in the bone marrow.Supported by grants CA 23334 and CA 23100 from the NCI and a grant from Boehringer Ingelheim Ltd. Presented as an abstract at the American Association for Cancer Research Meeting in Los Angeles, CA, May 7–10, 1986. This research is conducted in part by the Clayton Foundation for Research, California Division. Dr. Howell is a Clayton Foundation Investigator     

Clinical pharmacology of vinzolidine

Summary Vinzolidine (VZL), a new semisynthetic vinca alkaloid, was studied by using ³H-labeled VZL administered PO in four patients. At single doses from 1.5 to 36.5 mg/m² (0.034–0.919 mg/kg) radioactivity was rapidly absorbed with a half-life of absorption of 1 h and a peak at 4 h. Plasma decay of radiolabel followed a biphasic pattern with an alpha half-life of 10.48 h and a beta half-life of 172 h. The apparent plasma clearance was dose-dependent.The total radiolabel recovered was 52.9%±11.4% of the administered label, with 90% in the feces.HPLC analysis revealed that in all extracted plasma, urine, and feces the predominant material was unchanged VZL. Several metabolites were observed but not identified.Presented in part at the 75th Annual Meeting of the American Association for Cancer Research, May 19, 1984, Toronto, Canada, and at the 2nd International Conference on Malignant Lymphoma, Current Status and Prospects, June 19, 1984, Lugano, SwitzerlandSupported by Eli Lilly & Co., and The Don Monti Memorial Research Foundation