Effects of combretastatin A-4 prodrug against a panel of malignant human B-lymphoid cell lines

Combretastatin A-4 (CA-4) is one of a family of compounds isolated from the South African willow tree Combretum caffrum. CA-4 was found to be active against murine melanoma and a variety of other human solid tumors. For the first time, we report the effect of CA-4 against a panel of malignant human B-lymphoid cell lines [early pre-B acute lymphoblastic leukemia (Reh), diffuse large cell lymphoma (WSU-DLCL2), chronic lymphocytic leukemia (WSU-CLL) and Waldenstrom's macroglobulinemia (WSU-WM)]. Our results indicate, using the prodrug form of CA-4, a concentration-dependent growth inhibition in all tested cell lines, although WSU-DLCL2 was more sensitive. Exposure to 4 nM CA-4 for 96 h induced 77% growth inhibition in Reh, 86% in WSU-CLL and 92% in WSU-WM. When used against the WSU-DLCL2 cell line, this same concentration of CA-4 was completely toxic. Morphological examination showed CA-4 induced the formation of giant, multinucleated cells, a phenomenon commonly found in mitotic catastrophe. Only minimal numbers of cells showing characteristics of apoptosis were detected. In WSU-DLCL2 cells, CA-4 (3 nM) induced the highest apoptosis (5%) after 48 h, while the percentage of dead cells was approximately 47%. Exposure of Reh, WSU-CLL, WSU-WM and WSU-DLCL2 cells for 24 h to 5 nM CA-4 induced 19, 28, 57 and 75% G2/M arrest, as determined by flow cytometry, respectively. Based on these preliminary studies, we believe that mitotic catastrophe is the predominant mechanism by which CA-4 induces cell death rather than apoptosis. Further studies to elucidate the mechanisms of CA-4 activity in vitro and in vivo are currently under investigation in our laboratory.     

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.     

Synthesis and cytotoxic activity of certain trisubstituted azetidin-2-one derivatives as a <Emphasis Type="Italic">cis</Emphasis>-restricted combretastatin A-4 analogues

Novel series of 1,3,4-trisubstituted azetidin-2-one derivatives 8a–p were synthesized and proposed as cytotoxic agents acting via inhibition of tubulin at the colchicine binding site. The design of the target compounds was based upon modification in the structure of the vascular targeting agent combretastatin A-4 (CA-4). The cis double bond linker in CA-4 was replaced with the azetidin-2-one ring aiming to prevent the cis/trans isomerization that suppresses the activity of CA-4, thereby enhancing its antiproliferative activity. All new compounds were investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by four most potent compounds 8g, 8j, 8n and 8o was also evaluated. The synthesis of the final targets was achieved adopting Staudinger reaction. Molecular modeling studies were performed to rationalize the biological results.     

The metabolism of eugenol in man

1. The metabolism of eugenol (4-hydroxy-3-methoxy-allylbenzene) was investigated in male and female healthy volunteers. It was rapidly absorbed and metabolized after oral administration and was almost completely excreted in the urine within 24 h. Unmetabolized eugenol excreted in urine amounted to less than 0.1% of the dose. 2. The urine contained conjugates of eugenol and of nine metabolites. The structures of these metabolites, elucidated using g.l.c.-mass spectrometry, and by comparison with synthetic reference compounds, were identified as: eugenol, 4-hydroxy-3-methoxyphenyl-propane, cis- and trans-isoeugenol, 3-(4-hydroxy-3-methoxyphenyl)-propylene-1,2-oxide, 3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol, and 3-(4-hydroxy-3-methoxyphenyl)-propionic acid. 3. The structures of the following metabolites were tentatively deduced from mass spectra only, as reference compounds were not available: 3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-allylbenzene, 3-(6?-mercapto-4-hydroxy-3-methoxyphenyl)-propane, and 2-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-propionic acid. 4. The amounts of the individual metabolites excreted were determined by g.l.c. Some 95% of the dose was recovered in the urine, most of which (greater than 99%) consisted of phenolic conjugates; 50% of the conjugated metabolites were eugenol-glucuronide and sulphate. Other metabolic routes observed were the epoxide-diol pathway, synthesis of a thiophenol and of a substituted propionic acid, allylic oxidation, and migration of the double bond.     

Highly potent triazole-based tubulin polymerization inhibitors

We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors that contain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond in combretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerization inhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant (MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, as exemplified by compound 7, conferred optimal properties among this series. Computer docking and molecular simulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likely to interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It is hoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles as potential anti-cancer therapeutic agents.     

Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization

An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a greater than 8a greater than 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a greater than 8a greater than 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.     

Synthesis and characterization of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene) benzenamine derivatives as potent antifungal agents

In the present study, a series of (Z)-N-(1-[2-{3-[(dimethylamino)methyl)]-2-methoxyphenyl}-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl]ethylidene)benzenamine derivatives have been synthesized and characterized by IR, 1H NMR and 13C NMR spectra. All the synthesized compounds were evaluated for their antifungal activity and were compared with the standard drug, clotrimazole. The compounds demonstrated excellent to weak antifungal activity. Among the synthesized derivatives, 4f and 4h showed significant activity and 4c exhibited moderate activity against Candida albicans, Candida tropicalis and Aspergillus niger as compared with the standard antifungal agent - clotrimazole. The minimum inhibitory concentration of the compounds was in the range of 1.62-25 microg/mL against fungi. Furthermore, the substitution of chloro, nitro and methoxy groups at para position of benzene moiety play an important role in enhancing the antifungal activity of this class of compounds.     

新型二氢呋喃类化合物的合成及抑制血小板聚集活性研究

目的 研究2-（4-甲氧基苯基）-4-乙烯基-2,5-二氢呋喃-3-羧酸及其衍生物的合成及抗血小板凝集活性.方法 设计合成未见报道的目标化合物17个,应用1H-NMR、MS对得到的目标化合物进行结构鉴定,采用Born方法对目标化合物进行体外抗凝血活性测试.结果 合成得到2-（4-甲氧基苯基）-4-乙烯基-2,5-二氢呋喃-3-羧酸及其衍生物17个,所有目标化合物均具有优于对照药MCI-154的抗血小板凝集活性.结论 2-（4-甲氧基苯基）-4-乙烯基-2,5-二氢呋喃-3-羧酸及其衍生物具有较好的抗凝血药理活性,其中化合物（3）,（6）和（10）的活性分别是到对照药MCI-154的22.2,12.8和8.6倍,具有很强的开发应用前景.     

Synthesis and structure-activity relationships of a new oral cephalosporin, BMY-28100 and related compounds

The synthesis and structure-activity relationships of 7-[D-alpha-amino-alpha-(4-hydroxyphenyl)-acetamido]-3-[(Z)-1-propenyl]- 3-cephem-4-carboxylic acid (BMY-28100) and its analogs in the 3- and 7-side chains are described. The 3-(substituted-propenyl) groups were introduced by the Wittig reaction of the 3-phosphoniomethyl cephems which were derived from the 3-chloromethyl derivatives. The reaction gave predominantly the cis isomer regarding the 3-side chain. The cis and trans isomers showed characteristic UV and 1H NMR spectra. Most of cephems of this series were well-absorbed orally and more active both in vitro and in vivo than cephalexin and cefaclor against Gram-positive organisms. Their Gram-negative activity varied depending on the 3- and 7-substituents. Compounds with a cis-propenyl group showed the best Gram-negative activity among the 3-alkenyl analogs prepared, whereas the D-4-hydroxyphenylglycyl and D-4-hydroxy-3-methoxyphenylglycyl substitutions in the 7-side chain were found suitable to improve the Gram-negative activity of 3-cis-propenyl series of cephalosporins to the level favorably compared with that of cefaclor. The 3,4-dihydroxyphenyl analog was found to be metabolized in vivo to the 4-hydroxy-3-methoxyphenyl derivative and, therefore, showed nearly the same in vivo activity as that of the latter. BMY-28100 was selected for further evaluation and the results will be reported in the subsequent paper.     

Homoisoflavonoids: natural scaffolds with potent and selective monoamine oxidase-B inhibition properties

A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a-w, 3-benzyl-4H-chromen-4-ones 2a-g, and 3-benzylchroman-4-ones 3a-e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones 1a-w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a-e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a-g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selective inhibitor selegiline. Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l.     

4-Aryl-4H-naphthopyrans derivatives: one-pot synthesis,evaluation of Src kinase inhibitory and anti-proliferative activities

Background

A series of 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives were synthesized and evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines.

Methods

The one-pot, three-component reaction of α or β-naphthol, malonitrile and an aromatic aldehyde in the presence of diammonium hydrogen phosphate was afforded the corresponding 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives, All target compounds were evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines.

Results

Among all tested compounds, unsubstituted 4-phenyl analog 4a showed Src kinas inhibitory effect with IC₅₀ value of 28.1 μM and was the most potent compound in this series. In general, the compounds were moderately active against BT-20. 3-Nitro-phenyl 4e and 3-pyridinyl 4h derivatives inhibited the cell proliferation of BT-20 cells by 33% and 31.5%, respectively, and found to be more potent compared to doxorubicin (25% inhibition of cell growth).

Conclusion

The data indicate that 4-aryl-4H-naphthopyrans scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds.     

Synthesis,cytotoxicity and antitumor activity of 2,3-diarylcyclopent-2-ene-1-ones

Two series of 2,3-diarylcyclopent-2-ene-1-ones including 2-aryl-3-(2,5-dihydroxyphenyl)cyclopent-2-ene-1-ones (2a-2f) and 3-aryl-2-3',4',5'-trimethoxyphenyl)cyclopent-2-ene-1-one (3a-3j) were synthesized and evaluated for the cytotoxicity against three tumor cell lines; B16F10, HCT116 and A431. It was found that the 3,4,5-trimethoxy substituent was optimal for the bioactivity of compounds in series 2. Meanwhile, compounds in series 3 exhibited the most potent cytotoxicity with 3-aryl ring being 4-methoxyphenyl (compound 3f), (3-hydroxy-4-methoxy)phenyl (compound 3e), or (3-amino-4-methoxy)phenyl (compound 3j).     

5-allyl-9-oxobenzomorphans. 3. Potent narcotic antagonists and analgesics-antagonists in the series of substituted 2',9beta-dihydroxy-6,7-benzomorphans.

5-Allyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan methiodide (1) has been converted in a selective two-step process to the corresponding 9beta-hydroxy intermediates 4 and 6, which in turn were transformed via modified von Braun demethylation-acylation to the amides 11 and 21, respectively. These were reduced and demethylated to give a series of 5-allyl-2',9beta-dihydroxy-2-substituted 6,7-benzomorphans 13 and 23, some of which have been found to be highly potent narcotic antagonists and/or analgesics. The resolution of the most interesting compounds (23a and 23b) and pharmacological properties of the optical isomers are also described. Reduction of the double bond in 13 and 23 to give 14 and 24, with one exception, did not appreciably alter pharmacological profiles, while cyclization to the tetrahydrofuranobenzomorphans 25 substantially reduced the level of activities.     

Studies on the synthesis of condensed pyridazine derivatives. I. Synthesis and benzodiazepine receptor binding studies of 2-substituted-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-ones and related compounds

A series of 2-substituted-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-ones and related compounds were synthesized and tested for their ability to displace [3H]diazepam from rat brain membranes. Among them, compounds bearing 4-methoxyphenyl, 4-chlorophenyl, or 4-methylphenyl group at the position-2 were found to have high affinity to the benzodiazepine receptor. 2-(4-Methoxyphenyl)-9-methyl- and 2-(4-methoxyphenyl)-9-methoxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin- 3(2H)-ones (8b-14 and 8b-15, respectively) showed a potent affinity comparable to that of diazepam. These results suggest that a topographical planarity or pseudoplanarity of these molecules is essential for high affinity to the benzodiazepine receptor. The structure-activity relationships are discussed.     

Synthesis and evaluation of antibacterial activity of some 2-[[alpha-(4-substituted benzoyloxy)-alpha-phenylacetyl or methylacetyl]amino]-5-(4-methoxyphenyl)- 1,3,4-oxadiazoles

In this study, a new series of 1-[[alpha-(4-substitutedbenzoyloxy)-alpha-phenylacetyl or methylacetyl]amino]-5-(4-methoxyphenyl)-1,3,4-oxadiazoles were obtained by condensation of 2-[(alpha-chloro-alpha-phenylacetyl or alpha-bromopropionyl)amino]-5-(4-methoxyphenyl)1,3,4-oxadiazoles with sodium salts of 4-substituted benzoic acids. Structures of the compounds were assigned on the basis of spectral data (UV, IR, 1H NMR, El MS) and elemental analyses. The antibacterial activities of the novel compounds against Staphylococcus aureus ATCC 6538. Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri and Proteus mirabilis and antifungal activity against Candida albicans ATCC 10231 were tested using disk diffusion method. Compounds 4a, 4d and 4g were found to be active against S. aureus ATCC 6538 (MIC, 78, 39 and 78 microg ml(-1), respectively) and compound 4e against S. epidermidis ATCC 12228 (MIC, 156 microg ml(-1)).     

Synthesis,anticonvulsant and neurotoxicity evaluation of some new pyrimidine-5-carbonitrile derivatives

A series of 2-[2-(substituted benzylidene) hydrazinyl]-4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile (3–16) were synthesized by refluxing 2-hydrazino-4-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile (2) with different substituted aromatic aldehydes in glacial acetic acid and absolute alcohol mixture (8:2). The compounds were evaluated for their anticonvulsant and neurotoxicity effect. In MES test compounds 2-[2-(4-bromo-benzylidene)-hydrazinyl]-4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile (5), 2-[2-(4-hydroxy-benzylidene)-hydrazinyl]-4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile (9), and 2-[2-(3-fluoro-benzylidene)-hydrazinyl]-4-(4-methoxyphenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile (16) were found to be highly active at a dose level of 30 mgkg⁻¹ at 0.5 h time interval, indicating their ability to prevent seizure spread at a relatively low dose.     

Human dose-excretion studies with pyrethroid insecticides cypermethrin and alphacypermethrin: Relevance for biological monitoring

1. Dose-excretion studies with cypermethrin (as a 1:1 cis/trans mixture) and alphacypermethrin (one of the two disastereoisomer pairs which constitute cis cypermethrin) were carried out with, in each case, two volunteers per dose level. The studies included (a) single oral alphacypermethrin doses of 0˙25 mg, 0˙50 mg and 0˙75 mg followed by repeated alphacypermethrin doses at the same levels, daily for five days, (b) repeated oral cypermethrin doses of 0˙25 mg, 0˙75 mg and 1˙5mg daily for five days, and (c) a single dermal application of 25 mg cypermethrin to the forearm. Urine was monitored for the free and conjugated 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid before and after dosing.

2. Metabolism and rate of excretion of a single oral dose of alphacypermethrin was similar to that of cis cypermethrin, on average, 43% of the dose was excreted as the cyclopropanecarboxylic acid in the first 24 h urine. There was no increase in urinary metabolite excretion when alphacypermethrin was administered as a repeated oral dose. Subjects excreted, on average, 49% of the dose as the cyclopropanecarboxylic acid in the subsequent 24 h periods after dosing.

3. There was no increase in the urinary cyclopropanecarboxylic acid excretion when cypermethrin was administered as a repeated oral dose. Subjects excreted, on average, 72% of the trans isomer dose and 45% of the cis isomer dose respectively in the subsequent 24 h periods after dosing.

4. Approximately 0˙1% of the applied dermal dos>e of 25 mg cypermethrin was excreted within 72 h as the urinary cyclopropanecarboxylic acid. No conclusions can be drawn from such urinary excretion data as to the concentration of cypermethrin and its metabolites in the skin or other organs, or the possibility of other routes of metabolism or excretion.     

Anticoagulante 2,5-Diarylcyclopent-4-en-1,3-dione

Anticoagulant 2,5-Diarylcyclopent-4-ene-1,3-diones Seven title compounds were synthesized and tested for their anticoagulant activities. With five of them prothrombin levels below 25 % of normal were achieved in rats 12–48 h after a single oral dose. The most active compound 1a showed this effect after a dose of 43 mg/kg. By hydrogenation of the double bond, removal of the 4-hydroxy group and replacement of the carbonyl function at position 1 by a sulfonyl group, compounds without anticoagulant activity were obtained.     

Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents

A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.     

Human dose-excretion studies with pyrethroid insecticides cypermethrin and alphacypermethrin: relevance for biological monitoring

1. Dose-excretion studies with cypermethrin (as a 1:1 cis/trans mixture) and alphacypermethrin (one of the two disastereoisomer pairs which constitute cis cypermethrin) were carried out with, in each case, two volunteers per dose level. The studies included (a) single oral alphacypermethrin doses of 0.25 mg, 0.50 mg and 0.75 mg followed by repeated alphacypermethrin doses at the same levels, daily for five days, (b) repeated oral cypermethrin doses of 0.25 mg, 0.75 mg and 1.5 mg daily for five days, and (c) a single dermal application of 25 mg cypermethrin to the forearm. Urine was monitored for the free and conjugated 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid before and after dosing. 2. Metabolism and rate of excretion of a single oral dose of alphacypermethrin was similar to that of cis cypermethrin, on average, 43% of the dose was excreted as the cyclopropanecarboxylic acid in the first 24 h urine. There was no increase in urinary metabolite excretion when alphacypermethrin was administered as a repeated oral dose. Subjects excreted, on average, 49% of the dose as the cyclopropanecarboxylic acid in the subsequent 24 h periods after dosing. 3. There was no increase in the urinary cyclopropanecarboxylic acid excretion when cypermethrin was administered as a repeated oral dose. Subjects excreted, on average, 72% of the trans isomer dose and 45% of the cis isomer dose respectively in the subsequent 24 h periods after dosing. 4. Approximately 0.1% of the applied dermal dose of 25 mg cypermethrin was excreted within 72 h as the urinary cyclopropanecarboxylic acid. No conclusions can be drawn from such urinary excretion data as to the concentration of cypermethrin and its metabolites in the skin or other organs, or the possibility of other routes of metabolism or excretion.