RESUMO
To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (rs = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.
Assuntos
Citocromo P-450 CYP2C19/genética , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/biossíntese , Interações Ervas-Drogas , Hypericum , Fenilpropionatos/farmacocinética , Extratos Vegetais/administração & dosagem , Piridazinas/farmacocinética , Administração Oral , Adulto , Estudos Cross-Over , Citocromo P-450 CYP2C19/metabolismo , Esquema de Medicação , Indução Enzimática , Feminino , Genótipo , Alemanha , Voluntários Saudáveis , Humanos , Masculino , Midazolam/administração & dosagem , Midazolam/farmacocinética , Farmacogenética , Fenótipo , Fenilpropionatos/administração & dosagem , Fenilpropionatos/sangue , Piridazinas/administração & dosagem , Piridazinas/sangueRESUMO
INTRODUCTION: Because 30 to 70% of tumour patients use complementary and alternative medicines; herb-drug combinations are particularly frequent in this population. Some of these combinations can critically alter exposure of anti-neoplastic and palliative treatment. AREAS COVERED: This review summarises pharmacokinetic drug interactions caused by the herbal products most frequently used by tumour patients (garlic, ginkgo, ginseng, echinacea and St John's wort [SJW]). EXPERT OPINION: Herb-drug interactions, in general, and some interactions in particular (e.g., transporters, Phase II metabolism enzymes) are still poorly investigated and are difficult to evaluate because mixtures are administered with variable and often unspecified amounts of ingredients. Current evidence suggests that garlic and ginkgo can be safely co-administered, whereas CYP2C9 substrates (e.g., warfarin) should be monitored closely when ginseng therapy is started. Echinacea can induce drug metabolism mediated by CYP3A, but most likely relevant when administered with substances with a narrow therapeutic index or low oral bioavailability. The most relevant herbal perpetrator drug is SJW, which has substantial impact on CYP3A4- and CYP2C9-mediated metabolism and P-glycoprotein-mediated transport. This may lower exposure of co-administered drugs by up to 70%. Such an interaction is expected to occur with most of the tyrosine kinase inhibitors, but current evidence is limited.
Assuntos
Antineoplásicos/farmacocinética , Interações Ervas-Drogas , Neoplasias/tratamento farmacológico , Fitoterapia/métodos , Preparações de Plantas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ensaios Clínicos como Assunto , Terapias Complementares/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Echinacea/química , Alho/química , Ginkgo biloba/química , Humanos , Hypericum/química , Panax/químicaRESUMO
PURPOSE: The aim of this clinical study was to investigate a previously proposed mechanism of ketoconazole-mediated inhibition of cytochrome P450 3A (CYP3A) induction. METHODS: A two-phase, randomized, cross-over, open, mono-centre trial was carried out. Participants received ketoconazole and St John's wort for 8 days to study the proposed suppression of St John's wort-mediated induction of CYP3A at the transcriptional level. In the second phase, we studied the inhibitory effect of a single dose of ketoconazole directly at the enzyme level during CYP3A induction by St John's wort. Midazolam served as a marker substance of CYP3A activity using an established limited sampling strategy. RESULTS: After 8 days of simultaneous ketoconazole and St John's wort administration, CYP3A-mediated midazolam metabolism was strongly inhibited (81 % decrease in clearance). Following the induction of CYP3A with St John's wort (6.6-fold increase in clearance on day 8), a single dose of ketoconazole strongly inhibited midazolam metabolism to the same degree (82 % decrease in clearance in relation to baseline). An induction of midazolam metabolism was observed after discontinuation of both drugs in both study phases. These results apparently contradict the in vitro results where ketoconazole showed an inhibitory effect on the transcription of CYP3A genes. CONCLUSIONS: Ketoconazole is a strong inhibitor of CYP3A, also when used concomitantly with St John's wort. In therapeutic doses it does not inhibit pregnane X receptor-mediated induction of CYP3A in vivo.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A/biossíntese , Inibidores Enzimáticos/administração & dosagem , Hypericum , Cetoconazol/administração & dosagem , Extratos Vegetais/administração & dosagem , Receptores de Esteroides/efeitos dos fármacos , Adulto , Área Sob a Curva , Biotransformação , Estudos Cross-Over , Citocromo P-450 CYP3A/genética , Esquema de Medicação , Interações Medicamentosas , Indução Enzimática , Alemanha , Humanos , Hidroxilação , Masculino , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/análogos & derivados , Midazolam/farmacocinética , Pessoa de Meia-Idade , Plantas Medicinais , Receptor de Pregnano X , Receptores de Esteroides/metabolismo , Especificidade por Substrato , Transcrição Gênica/efeitos dos fármacos , Adulto JovemRESUMO
FOLFOX is a cytostatic drug combination for adjuvant treatment of colorectal cancer (CRC) consisting of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. The mechanism of synergistic interaction of these drugs is poorly understood and little is known concerning the role of drug transporters and the impact of oxaliplatin metabolites oxalate and dichloro-diaminocyclohexane platinum. We therefore investigated the influence of FOLFOX components on drug transporter expression by quantitative real-time polymerase chain reaction and on the efficacy of each FOLFOX component by proliferation assay in the CRC model cell line LS180. Control experiments with transporter over-expressing cell lines were used to assess the significance of important transporters for the cytostatic activity of FOLFOX components. Moreover, we assessed the pharmacological contribution of the oxalato-ligand to the effect of oxaliplatin. FOLFOX components led to several alterations in expression of drug transporters. For instance, 5-FU significantly suppressed ATP7B and human organic cation transporter 2 and increased multidrug resistance-associated protein (MRP) 2 mRNA expression (5.8-fold). This was accompanied by a significant sensitisation to oxaliplatin. Over-expression of certain ABC-transporters (BCRP/ABCG2, MRP2/ABCC2 or MRP3/ABCC3) was demonstrated to be beneficial for the efficacy of oxaliplatin. The results obtained indicate that both down- and up-regulations of drug transporters could favour synergistic action of this drug combination. Moreover, oxaliplatin metabolite oxalate seems to positively modulate oxaliplatin's action as elucidated by median effect analysis. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/biossíntese , Adenosina Trifosfatases/biossíntese , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte de Cátions/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Acetilcisteína/farmacologia , Adenosina Trifosfatases/genética , Animais , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Fluoruracila/farmacologia , Glutationa/metabolismo , Humanos , Leucovorina/farmacologia , Camundongos , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Compostos Organoplatínicos/metabolismo , Compostos Organoplatínicos/farmacologia , Oxaliplatina , RNA Mensageiro/biossínteseRESUMO
PURPOSE: The frequency of drug administration errors and incompatibilities between intravenous drugs before and after an intervention in an intensive care unit (ICU) is discussed. METHODS: Critically ill adult patients with intoxications, multiorgan failure, and serious infections were included in a retrospective analysis and in a prospective two-period, one-sequence study. In the retrospective analysis, the most frequent brands of i.v. medications used in the ICU of a gastroenterologic department in a teaching hospital were identified. All possible combinations and resulting incompatibilities were defined. Based on the results, a standard operating procedure (SOP) was established to prevent frequent and well-documented incompatibilities among i.v. medications. In the prospective study, trained pharmacy students assessed incompatible coinfusions before and after SOP implementation. RESULTS: In the retrospective analysis of 100 patients, 3617 brands of drug pairs were potentially given concurrently through one i.v. line and 7.2% of the drug pairs were incompatible. Antibiotics, such as piperacillin-tazobactam and imipenem-cilastatin, were the most frequent incompatible drug pairs. The newly developed SOP mandated that administration of these drugs be separated from all other drugs and suggested the use of an idle i.v. line for infusion whenever possible. In the prospective study of 50 patients, the frequency of incompatible drug pairs was reduced by the time of intervention from 5.8% to 2.4%. Incompatible drug pairs that were governed by the new SOP were reduced from 1.9% to 0.5%. CONCLUSION: Administration of incompatible i.v. drugs in critically ill patients was frequent but significantly reduced by procedural interventions with SOPs.
Assuntos
Incompatibilidade de Medicamentos , Unidades de Terapia Intensiva , Guias de Prática Clínica como Assunto , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Protocolos Clínicos , Estado Terminal , Alemanha , Hospitais com mais de 500 Leitos , Hospitais de Ensino , Humanos , Infusões Intravenosas , Erros de Medicação/prevenção & controle , Serviço de Farmácia Hospitalar/organização & administração , Estudos Prospectivos , Estudos RetrospectivosRESUMO
In cell culture systems with aqueous buffers, concentration-response curves to lipophilic inhibitors are difficult to establish because plateau effects (Imax) are often not reached because of limited drug solubility. Consequently, the inhibitory potency of a compound will not be definable using IC50 values (concentration exerting 50% of Imax). Since alternative potency measures f2 values, the concentrations required to double baseline signals have been proposed. Using both methods, we reevaluated the concentration-response curves of calcein assays with 78 compounds in three different cell culture systems and found a close correlation between both methods (r(s) = 0.93-0.99, p < or = 0.0028). These findings suggest that f2 values are a valuable alternative to define rank orders of highly lipophilic inhibitors as a basis for the prediction of pharmacological interaction properties in clinical settings. Although it was only tested for inhibition of P-glycoprotein, it seems likely that this method may be transferred to other assays with other proteins.