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1.
Regul Toxicol Pharmacol ; 145: 105494, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37748702

RESUMO

Health-based exposure limits (HBELs) are derived for leachables from polymeric components that interact with the drug substance which exceed a safety concern threshold (SCT). However, given the nature of leachables, there is not always chemical-specific toxicology data. Read-across methodology specific to extractables and leachables (E&Ls) was developed based on survey data collected from 11 pharmaceutical companies and methodology used in other industries. One additional challenge for E&L read-across is most toxicology data is from the oral route of administration, whereas the parenteral route is very common for the leachable HBEL derivation. A conservative framework was developed to estimate oral bioavailability and the corresponding oral to parenteral extrapolation factor using physical chemical data. When this conservative framework was tested against 73 compounds with oral bioavailability data, it was found that the predicted bioavailability based on physico-chemical properties was conservatively greater than or equal to the experimental bioavailability 79% of the time. In conclusion, an E&L read-across methodology has been developed to provide a consistent, health protective framework for deriving HBELs when toxicology data is limited.


Assuntos
Contaminação de Medicamentos , Embalagem de Medicamentos , Preparações Farmacêuticas/química , Administração Oral
2.
Regul Toxicol Pharmacol ; 118: 104802, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33038429

RESUMO

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.


Assuntos
Compostos Benzidrílicos/análise , Hidroxitolueno Butilado/análogos & derivados , Hidroxitolueno Butilado/análise , Contaminação de Medicamentos , Embalagem de Medicamentos , Preparações Farmacêuticas/análise , Fenóis/análise , Fosfitos/análise , Testes de Toxicidade , Animais , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/toxicidade , Hidroxitolueno Butilado/farmacocinética , Hidroxitolueno Butilado/toxicidade , Cricetinae , Árvores de Decisões , Humanos , Camundongos , Segurança do Paciente , Fenóis/farmacocinética , Fenóis/toxicidade , Fosfitos/farmacocinética , Fosfitos/toxicidade , Ratos , Medição de Risco , Toxicocinética
3.
Regul Toxicol Pharmacol ; 90: 262-276, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28958912

RESUMO

The applicability of the Direct Peptide Reactivity Assay (DPRA), the KeratinoSens™ assay and the human cell line activation test (OECD Test Guidelines 442C, 442D, 442E) in predicting the skin sensitising potential of nine lipid (bio)chemicals was investigated. The results from the three assays were integrated using a published prediction model (PM), by which skin sensitisation is predicted if at least two of the three assays yield positive results. Of the eight test substances that were classified as non-sensitisers using available Guinea Pig Maximisation Test (GPMT) data, only five were correctly predicted as 'negative' in the PM. (However, only two were correctly predicted as 'negative' in the murine Local Lymph Node Assay.) The one lipid (bio)chemical that tested positive in the GPMT was also positive applying the PM. Based upon the outcome of the present study, lipid (bio)chemicals with a log Kow up to 7-8 appear amenable to the three assays. However, solubility problems, that were not evident initially, affected the performance of the DPRA. Further investigations are merited to address the conclusiveness of negative test results with concurrent lack of cytotoxicity in the in vitro assays, to evaluate if poorly soluble substances come into contact with the cells.


Assuntos
Alérgenos/imunologia , Alternativas aos Testes com Animais/métodos , Bioensaio/métodos , Dermatite Alérgica de Contato/etiologia , Lipídeos/imunologia , Animais , Linhagem Celular , Cobaias , Humanos , Técnicas In Vitro/métodos , Lipídeos/química , Camundongos , Modelos Biológicos , Medição de Risco , Pele/efeitos dos fármacos , Pele/imunologia , Testes Cutâneos/métodos , Solubilidade , Especificidade da Espécie
4.
Regul Toxicol Pharmacol ; 81: 201-211, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27569203

RESUMO

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."


Assuntos
Produtos Biológicos/efeitos adversos , Produtos Biológicos/química , Liberação Controlada de Fármacos , Preparações Farmacêuticas/química , Segurança , Produtos Biológicos/administração & dosagem , Segurança Química , Humanos
5.
PDA J Pharm Sci Technol ; 76(5): 369-383, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35031541

RESUMO

The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient experimental toxicity data that is unlikely to result in an adverse health effect in humans, is important for evaluating extractables and leachables (E&Ls) as it guides analytical testing and minimizes the use of animal studies. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium, which consists of member companies that span biotechnology, pharmaceutical, and medical device industries, brought together subject matter expert toxicologists to derive TTC values for organic, non-mutagenic E&L substances when administered parenterally. A total of 488 E&L compounds from the ELSIE database were analyzed and parenteral point of departure (PPOD) estimates were derived for 252 compounds. The PPOD estimates were adjusted to extrapolate to subacute, subchronic, and chronic durations of nonclinical exposure and the lower fifth percentiles were calculated. An additional 100-fold adjustment factor to account for nonclinical species and human variability was subsequently applied to derive the parenteral TTC values for E&Ls. The resulting parenteral TTC values are 35, 110, and 180 µg/day for human exposures of >10 years to lifetime, >1-10 years, and ≤1 year, respectively. These parenteral TTCs are expected to be conservative for E&Ls that are considered non-mutagenic per ICH M7(R1) guidelines.


Assuntos
Biotecnologia , Nutrição Parenteral , Animais , Humanos , Preparações Farmacêuticas
6.
Arch Toxicol ; 85(5): 367-485, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21533817

RESUMO

The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission's Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e. toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitisation, and reproductive toxicity for which the Directive foresees that the 2013 deadline could be further extended in case alternative and validated methods would not be available in time. The selected experts were asked to analyse the status and prospects of alternative methods and to provide a scientifically sound estimate of the time necessary to achieve full replacement of animal testing. In summary, the experts confirmed that it will take at least another 7-9 years for the replacement of the current in vivo animal tests used for the safety assessment of cosmetic ingredients for skin sensitisation. However, the experts were also of the opinion that alternative methods may be able to give hazard information, i.e. to differentiate between sensitisers and non-sensitisers, ahead of 2017. This would, however, not provide the complete picture of what is a safe exposure because the relative potency of a sensitiser would not be known. For toxicokinetics, the timeframe was 5-7 years to develop the models still lacking to predict lung absorption and renal/biliary excretion, and even longer to integrate the methods to fully replace the animal toxicokinetic models. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time horizon for full replacement could not be estimated.


Assuntos
Alternativas aos Testes com Animais/tendências , Qualidade de Produtos para o Consumidor/legislação & jurisprudência , Cosméticos/normas , Testes de Toxicidade/tendências , Alternativas aos Testes com Animais/normas , Animais , Disponibilidade Biológica , Testes de Carcinogenicidade/métodos , União Europeia , Guias como Assunto , Humanos , Reprodutibilidade dos Testes , Medição de Risco/métodos , Medição de Risco/tendências , Pele/efeitos dos fármacos , Testes de Toxicidade/métodos
7.
Int J Nanomedicine ; 11: 5883-5896, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27877036

RESUMO

Combined individually tailored methods for diagnosis and therapy (theragnostics) could be beneficial in destructive diseases, such as rheumatoid arthritis. Nanoparticles are promising candidates for theragnostics due to their excellent biocompatibility. Nanoparticle modifications, such as improved surface coating, are in development to meet various requirements, although safety concerns mean that modified nanoparticles require further review before their use in medical applications is permitted. We have previously demonstrated that iron oxide nanoparticles with amino-polyvinyl alcohol (a-PVA) adsorbed on their surfaces have the unwanted effect of increasing human immune cell cytokine secretion. We hypothesized that this immune response was caused by free-floating PVA. The aim of the present study was to prevent unwanted immune reactions by further surface modification of the a-PVA nanoparticles. After cross-linking of PVA to nanoparticles to produce PVA-grafted nanoparticles, and reduction of their zeta potential, the effects on cell viability and cytokine secretion were analyzed. PVA-grafted nanoparticles still stimulated elevated cytokine secretion from human immune cells; however, this was inhibited after reduction of the zeta potential. In conclusion, covalent cross-linking of PVA to nanoparticles and adjustment of the surface charge rendered them nontoxic to immune cells, nonimmunogenic, and potentially suitable for use as theragnostic agents.


Assuntos
Células Sanguíneas/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Compostos Férricos/química , Nanopartículas de Magnetita/administração & dosagem , Álcool de Polivinil/química , Adsorção , Células Sanguíneas/metabolismo , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Nanopartículas de Magnetita/química
8.
Toxicol Lett ; 142(1-2): 89-101, 2003 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-12765243

RESUMO

4-Methylbenzylidene-camphor (4-MBC) is an organic sunscreen that protects against UV radiation and may therefore help in the prevention of skin cancer. Recent results on the estrogenicity of 4-MBC have raised concerns about a potential of 4-MBC to act as an endocrine disruptor. Here, we investigated the direct interaction of 4-MBC with estrogen receptor (ER) alpha and ERbeta in a series of studies including receptor binding, ER transactivation and functional tests in human and rat cells. 4-MBC induced alkaline phosphatase activity, a surrogate marker for estrogenic activity, in human endometrial Ishikawa cells. Interestingly, 4-MBC induced weakly ERalpha and with a higher potency ERbeta mediated transactivation in Ishikawa cells at doses more than 1 microM, but showed no distinct binding affinity to ERalpha or ERbeta. In addition, 4-MBC was an effective antagonist for ERalpha and ERbeta. In an attempt to put 4-MBC's estrogenic activity into perspective we compared binding affinity and potency to activate ER with phyto- and xenoestrogens. 4-MBC showed lower estrogenic potency than genistein, coumestrol, resveratrol, bisphenol A and also camphor. Analysis of a potential metabolic activation of 4-MBC that could account for 4-MBC's more distinct estrogenic effects observed in vivo revealed that no estrogenic metabolites of 4-MBC are formed in primary rat or human hepatocytes. In conclusion, we were able to show that 4-MBC is able to induce ERalpha and ERbeta activity. However, for a hazard assessment of 4-MBC's estrogenic effects, the very high doses of 4-MBC required to elicit the reported effects, its anti-estrogenic properties as well as its low estrogenic potency compared to phytoestrogens and camphor has to be taken into account.


Assuntos
Compostos de Benzilideno/farmacologia , Cânfora/análogos & derivados , Antagonistas de Estrogênios/farmacologia , Estrogênios/farmacologia , Isoflavonas , Receptores de Estrogênio/antagonistas & inibidores , Protetores Solares/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Anticarcinógenos/farmacologia , Cânfora/farmacologia , Dietilestilbestrol/farmacologia , Endométrio/citologia , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Ativação Enzimática/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Estrogênios não Esteroides/farmacologia , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Fitoestrógenos , Preparações de Plantas , Ratos , Ratos Wistar , Receptores de Estrogênio/agonistas , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/metabolismo
9.
Toxicol Lett ; 218(3): 246-52, 2013 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-23402938

RESUMO

The absorption and excretion of the insect repellent IR3535(®) was studied in human subjects (five males and five females) after dermal application of approx. 3g of a formulation containing 20% IR3535(®), i.e. the amounts of IR3535(®) applied were between 1.94 and 3.4 mmol/person (418-731 mg/person). Blood and urinary concentrations of IR3535(®) and its only metabolite, IR3535(®)-free acid, were determined over time. In plasma, concentrations of the parent compound IR3535(®) were at or below the limit of quantification (0.037 µmol/L). IR3535(®)-free acid peaked in plasma samples 2-6h after dermal application. Cmax mean values were 5.7 µmol/L in males, 3.0 µmol/L in females and 4.2 µmol/L in all volunteers. Mean AUC values were 41.6, 24.5 and 33.9 µmolL(-1)h in males, females and all subjects, respectively. In urine samples from all human subjects, both IR3535(®) and IR3535(®)-free acid were detectable, however, only very small amounts of IR3535(®) were found. Concentrations of IR3535(®)-free acid were several thousand-fold higher than the parent compound and peaked at the first two sampling points (4h and 8h after dermal application). Overall, IR3535(®) and IR3535(®)-free acid excreted with urine over 48 h representing 13.3 ± 3.05% of the dose applied. Since IR3535(®) is rapidly and extensively metabolized, and IR3535(®)-free acid has a low molecular weight and high water solubility, it is expected that urinary excretion of IR3535(®)-free acid and IR3535(®) represents the total extent of absorption of IR3535(®) in humans. Based on the results of this study, the skin penetration rate of IR3535(®) is 13.3% in humans after dermal application.


Assuntos
Repelentes de Insetos/administração & dosagem , Repelentes de Insetos/farmacocinética , Propionatos/administração & dosagem , Propionatos/farmacocinética , Administração Cutânea , Adulto , Área Sob a Curva , Biotransformação , Feminino , Humanos , Repelentes de Insetos/sangue , Repelentes de Insetos/toxicidade , Repelentes de Insetos/urina , Masculino , Taxa de Depuração Metabólica , Propionatos/sangue , Propionatos/toxicidade , Propionatos/urina , Absorção Cutânea , Adulto Jovem
10.
Reprod Toxicol ; 33(2): 133-41, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21798343

RESUMO

Coumarin and warfarin, two substances which are intensively metabolized in animals and humans, were tested for teratogenicity and embryo lethality in a 3-day in vitro assay using zebrafish embryos. Warfarin is a coumarin derivative, but in contrast to the mother substance warfarin has anticoagulant properties. Both substances produced teratogenic and lethal effects in zebrafish embryos. The LC(50) and EC(50) values for coumarin are 855 µM and 314 µM, respectively; the corresponding values for warfarin are 988 µM and 194 µM. For coumarin, three main or fingerprint endpoints (malformation of head, tail and growth retardation) were identified, whereas malformation of tail was the only fingerprint endpoint of warfarin. The analysis of the ratios between the zebrafish embryo effect concentrations of both substances and human therapeutic plasma concentrations confirmed the teratogenic potential of warfarin, as well as the equivocal status of coumarin.


Assuntos
Anticoagulantes/toxicidade , Cumarínicos/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Teratogênicos/toxicidade , Varfarina/toxicidade , Peixe-Zebra/anormalidades , Animais , Embrião não Mamífero/anormalidades
11.
Toxicology ; 281(1-3): 25-36, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21237239

RESUMO

Zebrafish embryos have been shown to be a useful model for the detection of direct acting teratogens. This communication presents a protocol for a 3-day in vitro zebrafish embryo teratogenicity assay and describes results obtained for 10 proteratogens: 2-acetylaminofluorene, benzo[a]pyrene, aflatoxin B(1), carbamazepine, phenytoin, trimethadione, cyclophosphamide, ifosfamide, tegafur and thio-TEPA. The selection of the test substances accounts for differences in structure, origin, metabolism and water solubility. Apart from 2-acetylaminofluorene, which mainly produces lethal effects, all proteratogens tested were teratogenic in zebrafish embryos exposed for 3 days. The test substances and/or the substance class produced characteristic patterns of fingerprint endpoints. Several substances produced effects that could be identified already at 1 dpf (days post fertilization), whereas the effects of others could only be identified unambiguously after hatching at ≥ 3 dpf. The LC50 and EC50 values were used to calculate the teratogenicity index (TI) for the different substances, and the EC20 values were related to human plasma concentrations. Results lead to the conclusion that zebrafish embryos are able to activate proteratogenic substances without addition of an exogenous metabolic activation system. Moreover, the teratogenic effects were observed at concentrations relevant to human exposure data. Along with other findings, our results indicate that zebrafish embryos are a useful alternative method for traditional teratogenicity testing with mammalian species.


Assuntos
Testes de Mutagenicidade/métodos , Teratogênicos/toxicidade , Peixe-Zebra , 2-Acetilaminofluoreno/toxicidade , Aflatoxina B1/toxicidade , Animais , Carbamazepina/toxicidade , Cinarizina/toxicidade , Ciclofosfamida/toxicidade , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Ifosfamida/toxicidade , Óvulo/efeitos dos fármacos , Piracetam/toxicidade , Tegafur/toxicidade , Tiotepa/toxicidade , Trimetadiona/toxicidade , Peixe-Zebra/embriologia
12.
Toxicology ; 275(1-3): 36-49, 2010 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-20566340

RESUMO

The zebrafish Danio rerio embryo test with metabolic activation (mDarT) was developed to assess the teratogenic effects of proteratogens. In this study induced rat liver microsomes (RLM) were used as a mammalian metabolic activation system (MAS), since they contain various cytochrome P450 (CYP) isoforms at high concentrations. Acetaminophen (APAP) is considered not to be teratogenic in vivo, however, in vitro teratogenic effects were observed, e.g. in rat whole embryo culture. The CYP2E1 activation of APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) mainly occurs, when the glucuronidation and sulfatation pathways are saturated. In vivo the soft electrophile NAPQI is usually inactivated by hepatic reduced glutathione (GSH), a soft nucleophile. In this study, we investigated the teratogenic and lethal effects of APAP after CYP activation in zebrafish embryos. In the test groups with APAP and metabolic activation 11.7+/-7.6% (2mM), 25.0+/-8.7% (4mM) and 50.0+/-21.8% (6mM) affected embryos were seen, reaching statistical significance at 4mM APAP. When embryos were exposed to 6mM APAP, MAS and 3mM GSH the percentage of affected embryos decreased to 6.7+/-5.8%. In contrast teratogenic and lethal effects of metabolically activated cyclophosphamide (CPA) could not be prevented by GSH addition, because the CPA metabolites are strong electrophiles, which preferentially bind to hard nucleophiles like DNA and RNA. The teratogenic and lethal effects of metabolically activated APAP observed in zebrafish embryos with our mDarT standard protocol could be explained by the lack of GSH as a detoxifying system. By adding GSH it was possible to mimic the situation in mammals and thus avoid teratogenic effects in zebrafish embryos.


Assuntos
Acetaminofen/metabolismo , Acetaminofen/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Animais , Biotransformação , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Masculino
13.
Toxicol Sci ; 104(1): 177-88, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18375544

RESUMO

The assessment of teratogenic effects of chemicals is generally performed using in vivo teratogenicity assays, for example, in rats or rabbits. We have developed an in vitro teratogenicity assay using the zebrafish Danio rerio embryo combined with an exogenous mammalian metabolic activation system (MAS), able to biotransform proteratogenic compounds. Cyclophosphamide (CPA) and ethanol were used as proteratogens to test the efficiency of this assay. Briefly, the zebrafish embryos were cocultured at 2 hpf (hours postfertilization) with the test material at varying concentrations, induced male rat liver microsomes and nicotinamide adenine dinucleotide phosphate (reduced) for 60 min at 32 degrees C under moderate agitation in Tris-buffer. The negative control (test material alone) and the MAS control (MAS alone) were incubated in parallel. For each test group, 20 eggs were used for statistical robustness. Afterward fish embryos were transferred individually into 24-well plates filled with fish medium for 48 h at 26 degrees C with a 12-h light cycle. Teratogenicity was scored after 24 and 48 hpf using morphological endpoints. No teratogenic effects were observed in fish embryos exposed to the proteratogens alone, that is, without metabolic activation. In contrast, CPA and ethanol induced abnormalities in fish embryos when coincubated with microsomes. The severity of malformations increased with increasing concentrations of the proteratogens. We conclude that the application of microsomes will improve and refine the D. rerio teratogenicity assay as a predictive and valuable alternative method to screen teratogenic substances.


Assuntos
Ciclofosfamida/toxicidade , Etanol/toxicidade , Teratogênicos/toxicidade , Testes de Toxicidade/métodos , Peixe-Zebra/anormalidades , Animais , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos
14.
Toxicol Appl Pharmacol ; 216(2): 331-8, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16806338

RESUMO

3-(4-Methylbenzylidene)camphor (4-MBC) is an UV-filter frequently used in sunscreens and cosmetics. Equivocal findings in some screening tests for hormonal activity initiated a discussion on a possible weak estrogenicity of 4-MBC. In this study, the toxicokinetics and biotransformation of 4-MBC were characterized in rats after oral administration. Male and female Sprague-Dawley rats (n = 3 per group) were administered single oral doses of 25 or 250 mg/kg bw of 4-MBC in corn oil. Metabolites formed were characterized and the kinetics of elimination for 4-MBC and its metabolites from blood and with urine were determined. Metabolites of 4-MBC were characterized by (1)H NMR and LC-MS/MS as 3-(4-carboxybenzylidene)camphor and as four isomers of 3-(4-carboxybenzylidene)hydroxycamphor containing the hydroxyl group located in the camphor ring system with 3-(4-carboxybenzylidene)-6-hydroxycamphor as the major metabolite. After oral administration of 4-MBC, only very low concentrations of 4-MBC were present in blood and the peak concentrations of 3-(4-carboxybenzylidene)camphor were approximately 500-fold above those of 4-MBC; blood concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were below the limit of detection. Blood concentration of 4-MBC and 3-(4-carboxybenzylidene)camphor peaked within 10 h after 4-MBC administration and then decreased with half-lives of approximately 15 h. No major differences in peak blood levels between male and female rats were seen. In urine, one isomer of 3-(4-carboxybenzylidene)hydroxycamphor was the predominant metabolite [3-(4-carboxybenzylidene)-6-hydroxycamphor], the other isomers and 3-(4-carboxybenzylidene)camphor were only minor metabolites excreted with urine. However, urinary excretion of 4-MBC-metabolites represents only a minor pathway of elimination for 4-MBC, since most of the applied dose was recovered in feces as 3-(4-carboxybenzylidene)camphor and, to a smaller extent, as 3-(4-carboxybenzylidene)-6-hydroxycamphor. Glucuronides of both metabolites were also present in feces, but partly decomposed during sample workup and were thus not quantified. The results show that absorbed 4-MBC undergoes extensive first-pass biotransformation in rat liver resulting in very low blood levels of the parent 4-MBC. Enterohepatic circulation of glucuronides derived from the two major 4-MBC metabolites may explain the slow excretion of 4-MBC metabolites with urine and the small percentage of the administered doses recovered in urine.


Assuntos
Cânfora/análogos & derivados , Protetores Solares/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Biotransformação , Cânfora/farmacocinética , Cânfora/toxicidade , Cânfora/urina , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Protetores Solares/análise , Protetores Solares/toxicidade
15.
Toxicol Appl Pharmacol ; 216(2): 339-46, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16814339

RESUMO

The toxicokinetics of 4-MBC after dermal administration were investigated in human subjects and in rats. Humans (3 male and 3 female subjects) were exposed to 4-MBC by topical application of a commercial sunscreen formulation containing 4% 4-MBC (w/w), covering 90% of the body surface and resulting in a mean dermal 4-MBC dose of 22 mg/kg bw. In rats, dermal 4-MBC doses of 400 and 2000 mg/kg bw were applied in a formulation using an occlusive patch for 24 h. Concentrations of 4-MBC and its metabolites were monitored over 96 h in plasma (rats and humans) and urine (humans). In human subjects, plasma levels of 4-MBC peaked at 200 pmol/ml in males and 100 pmol/ml in females 6 h after application and then decreased to reach the limit of detection after 24 h (females), respectively, 36 h (males). After dermal application of 4-MBC, peak plasma concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were 50-80 pmol/ml at 12 h and of 3-(4-carboxybenzylidene)camphor were 100-200 pmol/ml at 24 h. In male and female rats, peak plasma levels of 4-MBC were 200 (dose of 400 mg/kg bw) and 1 200 pmol/ml (dose of 2000 mg/kg bw). These levels remained constant for up to 24-48 h after dermal application. Peak plasma concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were 18,000 pmol/ml (males) and of 3-(4-carboxybenzylidene)camphor were 55,000 pmol/ml (females) between 48 and 72 h after application of the high dose of 4-MBC. In human subjects, only a small percentage of the dermally applied dose of 4-MBC was recovered in the form of metabolites in urine, partly as glucuronides. The obtained results suggest a more intensive biotransformation of 4-MBC in rats as compared to humans after dermal application and a poor absorption of 4-MBC through human skin.


Assuntos
Cânfora/análogos & derivados , Protetores Solares/farmacocinética , Administração Cutânea , Adulto , Animais , Área Sob a Curva , Cânfora/farmacocinética , Cânfora/toxicidade , Cânfora/urina , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Espectrometria de Massas por Ionização por Electrospray , Protetores Solares/análise , Protetores Solares/toxicidade
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