Larry M. Allen

Comparison of the human pharmacokinetics of VM-26 and VP-16, two antineoplastic epipodophyllotoxin glucopyranoside derivatives

Abstract The pharmacokinetics of the epipodophyllotoxin glucoside derivatives VM- 26 and VP- 16 have been evaluated in patients who have received 67–90 mg/m 2 of VM- 26 and 130–290 mg/m 2 of VP- 16 by short intravenous infusion. Whereas VM- 26 plasma decay kinetics follow a triexponential function and correspond to a three-compartment open model (mammillary type), VP- 16 plasma decay kinetics follow a biexponential decay and correspond to a two-compartment open model. The 3 -times-larger excretion rate ( 0·112 hr −1 ) and correspondingly larger renal clearance ( 13·6 ml/min) of VP- 16 over VM- 26 is correlated with the 3 -times-larger equitoxic dose ( 290 mg/m 2 ). Although VM- 26 appears to be slightly more metabolized ( 86% vs. 66% ) than VP- 16 , the much larger tolerated dose of VP- 16 can compensate for this difference. The discrepancy between the fraction of drug metabolized based on pharmacokinetic analysis and fraction of cumulative metabolite in the urine is explained on the grounds of extensive tissue storage of the parent compounds or their metabolites. The extent of tissue depot was evaluated by reference to body water and indicates it to be more extensive than some long-acting barbiturates. The integral coefficient for VM- 26 and VP- 16 in the central ( 1·14 vs 2·26 hr) and peripheral ( 3.74 vs 3·93 hr) compartment 2 suggest that the bioavailability of VM- 26 to be only slightly less than VP- 16 in those compartments. On the other hand, the bioavailability is greater for VM- 26 in peripheral compartment 3 compared to peripheral compartment 2 of VP- 16 .

EPEG, a new antineoplastic epipodophyllotoxin

Nine patients were studied with tritium‐labeled EPEG, a new epipodophyllotoxin antineoplastic agent. Four patients received 220 and 5 received 290 mg/sq m body surface area intravenously in 500 ml in 1 hr. Postinfusion plasma decay was biphasic with mean values for the parameters at 220 mg/sq m, A, 25.8 µglml; B, 3.35 µg/ml; α, 0.50 hr−1; β, 0.074 hr−1, and mean values at 290 mg/sq. m, A, 33.7 µg/ml; B, 4.35 µg/ml; α, 0.36 hr−1; ², 0.066 hr−1, Mean volume of distribution was 32.07% of body weight. Urinary recovery was 43.5%, of which 66.8% was unchanged drug. Penetration of drug into the cerebrospinal fluid was poor. The results indicate that both renal excretion and metabolism are important for elimination of the drug.

Absorption and Excretion of Cyanuric Acid in Long-Distance Swimmers

(1982). Absorption and Excretion of Cyanuric Acid in Long-Distance Swimmers. Drug Metabolism Reviews: Vol. 13, No. 3, pp. 499-516.

Clinical pharmacology of isophosphamide

The alkylating activity in the urine was measured in patients receiving a new antineoplastic cyclophosphomide analog, isophosphamide (IP), at doses of 2,900 to 5,000 mg per square meter body surface area (BSA) and compared with that of patients receiving 1,100 mg per square meter of cyclophosphamide (CP). Total excretion of alkylating activity after CP (1,l00 mg per square meter) lay between values for the 3,800 mg per square meter dose and the 5,000 mg per square meter dose of IP. The concentration of urinary alkylating activity was higher in patients who developed cystitis than in those who did not. Alkylating activity in the urine was unaltered by acetylcysteine bladder washout. Plasma alkylating activity was more persistent after 5,000 mg per square meter IP than after 1,100 mg per square meter CPo After [HC] IP 5,000 mg per square meter, the plasma half‐life was 13.79 hours, and the urinary recovery of radioactivity was 81.6%, of which 61.6% was unchanged drug. These values differ markedly from those published for CPo IP penetrated the blood‐brain barrier, but its metabolites did not. The greater propensity of IP than of CP to cause cystitis at apprOXimately equitoxic doses may be related to larger amounts of alkylating activity in urine of patients receiving IP. The greater dose of IP than of CP required to produce the same alkylating activity in urine correlates well with the differences in Km of the two drugs in an isolated microsomal enzyme system in vitro previously reported.

PTG, a new antineoplastic epipodophyllotoxin

The pharmacology of 4‐demethylepipodophyllotoxin 9‐(4, 6‐0‐thenylidene‐β‐Dglucopyranoside) PTG, a new anticancer drug, is reported. Six patients with advanced cancer were treated witli PTG (67 mg/m2 of body surface area intravenously) specifically labeled with tritium as the first dose of a weekly × 6 course. Recovery of drug in the urine was 44.49 ± 8.2% ofthe administered dose in 72 hr, of which 78.7 ± 5.1% was metabolite. Recovery in thefeces was 0 to 10.05% in 4 patients. Plasma decay fitted the equation Cp = Ae‐αt + Be‐βt + Ce‐yt by nonlinear least‐squares regression. Mean values for the parameters (after infusion) were A 14.3 ± 5.5, B 9.66 ± 3.98, C 2.44 ± 1.33 µg/ml; α 2.05 ± 1.25, β0.26 ± 0.15, σ 0.038 ± 0.016 hr‐1, Levels of drug in the cerebrospinal fluid (CSF) were <1 % of plasma levels in 3 patients at 24 hr after treatment and 27% in 1 patient who had had brain surgery and brain radiotherapy. Four of 4 patients considered evaluable for toxicity (>2 consecutive weekly doses) developed leukopenia (WBC <5,000/mm3). Mean nadir of WBC was 3,600/mm3. The most marked leukopenia (WBC, 2,300/mm3) was seen in the patient with the longest terminal phase plasma half‐life (38.5 hr). Two of 5 patients evaluable for response received clinical benefit (1 laryngeal carcinoma, 1 histiocytic lymphoma). It is concluded that PTG has a long terminal phase half‐life (11‐38.5 hr), is largely metabolized, and does not penetrate the normal blood‐brain barrier.

The bioavailability in man of ICRF-159 a new oral antineoplastic agent

The bioavailability of the antineoplastic agent, ICRF‐159, has been examined in 12 patients receiving the drug in single and subdivided dose schedules in an attempt to account for the differences in toxicity found with the different schedules clinically. Recovery of radioactivity in the urine after single large doses (13·3–19·4 g) was 8·5 ± 3·0% of the administered dose. After doses of 3·8–5·55 g recovery was 22·7 10±5% and after the same dose subdivided into 3 equal aliquots it was 52 ± 8·7%. Unrecovered radioactivity was largely accounted for in the faeces. Plasma radioactivity levels in 2 patients after high and low dose were equivalent. Toxicity of the drug paralleled urinary recovery of radioactivity. It is concluded that schedule dependence of toxicity of ICRF‐159 is at least partly due to bioavailability factors.

The interaction of the antineoplastic drug thalicarpine with aniline hydroxylase and microsomal cytochrome of rat liver.

Abstract1. The new antineoplastic agent thalicarpine inhibits aniline hydroxylase activity of rat liver microsomes.2. Pre-treatment with thalicarpine (75mg/kgx3) does not affect hepatic microsomal aniline hydroxylase activity, microsomal cytochrome P-450, cytochrome b5, NADPH cytochrome c reductase, RNA or nuclear DNA.3. Thalicarpine pre-treatment prevents the methylcholanthrene-induced increase in aniline hydroxylase, microsomal RNA and nuclear DNA, but does not affect the induction of cytochromes P-450 and b5.

Activation of the antineoplastic drug isophosphamide by rat liver microsomes

Isophosphamide (3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-1, 2, 3-oxazaphosphorine-2-oxide; NSC 109724; 2-4942 Asta Werke) a new antineoplasticanalogue of cyclophosphamide (2-[bis (2-chloroethyl)amino]tetrahydro-2H-l, 3, 2-oxazaphosphorine-2-oxide; Cytoxan; Endoxan) has shown antineoplastic activity in animal tumours (Brock, 1967) including tumors resistant to cyclophosphamide and appears in initial clinical trials to be superior to it in the treatment of small cell carcinoma of the lung in man (Scheef 1971). Cyclophosphamide is inactive in vitro and is activated to alkylating materials in vivo by the NADPH dependent mixed function oxidases of the liver microsomal fraction (Brock & Hohorst 1963). Isophosphamide is currently in clinical trial in this unit; we have, therefore, investigated the microsomal activation of this drug to compare it with that of its analogue. Subcellular fractions from the livers of 150g male Sprague-Dawley rats were prepared according to Creaven, Parke & Williams (1965). Both drugs (3 mM final concentration) were each incubated for 15 min in air with shaking with a fortified microsomal suspension (Sladek, 1971). Alkylating activity was assayed essentially as described by Friedman & Boger (1961) and is expressed as pmol of mechlorethamine equivalents (45 pmol of mechlorethamine has an absorbance of 0.40). Maximal activation of isophosphamide occurs with the microsomal fraction. Activities of other fractions as a percent of that of the microsomal fraction are: lo00 x g supernatant 92%, 10 000 x g supernatant 74%, 105 000 x g supernatant 15 %. No activation of either drug occurs in the absence of NADPH or an NADPH generating system. Inhibition of the activation of isophosphamide by other substrates of the microsomal oxidase system is 0 and 4% by 4 and 6 mM aniline, 20 and 30 % by 0.5 and 2.5 mM ethylmorphine, and 22 % by 3 mM 2,2-diethylaminoethyldiphenylvalerate (SKF 525-A) respectively. Vmax for the activation of the two drugs is the same for both (5.4 pmol/g liver per h); Km is 19.4 mM and 4.0 mM respectively (determined with the aid of a continuous simple linear regression program on a Olivetti Underwood Programma 101 ; r = 0-98 (isophosphamide) and 0.92 (cyclophosphamide). Like cyclophosphamide, isophosphamideis activated by asystem havingthecharacteristics of the microsomal mixed fuction oxidase system and is inhibited by substrates which show type I binding to microsomal haemoprotein. The lower affinity of isophosphamide for the activating enzyme is correlated with a higher toxic dose of it compared with cyclophosphamide in initial clinical trials (Scheef 1971). The expert technical assistance of Mrs. Gay P. Friedman is gratefully acknowledged.