RESUMO
AIMS: To compare the time profile of insulin detemir and human insulin concentrations in the interstitial fluid (ISF) of subcutaneous adipose tissue during constant i.v. infusion and to investigate the relationship between the pharmacokinetics of both insulin molecules in plasma and the ISF of subcutaneous adipose tissue. METHODS: During a 6-h hyperinsulinaemic-euglycaemic clamp (plasma glucose level 8 mmol/l) human insulin (21 and 42 pmol/min/kg) or insulin detemir (209 and 417 pmol/min/kg) were infused i.v. in eight rats per dose level. Open flow microperfusion (OFM) was used to continuously assess interstitial insulin concentrations in subcutaneous adipose tissue. RESULTS: At the lower infusion rate, insulin detemir appeared significantly later in the ISF than in the plasma (p < 0.05) and also appeared later in the ISF relative to human insulin (p < 0.005). CONCLUSIONS: By using OFM we were able to monitor albumin-bound insulin detemir directly in the ISF of subcutaneous tissue and confirm its delayed transendothelial passage to a peripheral site of action.
Assuntos
Líquido Extracelular/metabolismo , Hipoglicemiantes/farmacologia , Insulina de Ação Prolongada/farmacologia , Insulina Regular Humana/farmacologia , Perfusão/métodos , Gordura Subcutânea/efeitos dos fármacos , Animais , Glicemia/metabolismo , Líquido Extracelular/efeitos dos fármacos , Técnica Clamp de Glucose , Hipoglicemiantes/farmacocinética , Insulina Detemir , Insulina de Ação Prolongada/farmacocinética , Insulina Regular Humana/farmacocinética , Masculino , Perfusão/instrumentação , Ratos , Ratos Sprague-Dawley , Gordura Subcutânea/patologia , Fatores de TempoRESUMO
BACKGROUND: Sampling the dermal interstitial fluid (ISF) allows the pharmacokinetics and pharmacodynamics of dermatological drugs to be studied directly at their site of action. Dermal open-flow microperfusion (dOFM) is a recently developed technique that can provide minimally invasive, continuous, membrane-free (thus unfiltered) access to the dermal ISF. Herein, we evaluate the clinical applicability and reliability of novel wearable dOFM devices in a clinical setting. METHODS: Physicians inserted 141 membrane-free dOFM probes into the dermis of 17 healthy and psoriatic volunteers and sampled dermal ISF for 25 h by using wearable push-pull pumps. The tolerability, applicability, reproducibility, and reliability of multiple insertions and 25 h continuous sampling was assessed by pain scoring, physician feedback, ultrasound probe depth measurements, and 25 h-drift and variability of the sodium relative recovery. RESULTS: Insertion pain was moderate and decreased with each additional probe. Probe insertion was precise, although slightly deeper in lesional skin. The wearable push-pull pump enabled uninterrupted ISF sampling over 25 h with low variability. The relative recovery was drift-free and highly reproducible. CONCLUSION: dOFM sampling devices are tolerable and reliable for prolonged continuous dermal sampling in a multiprobe clinical setting. These devices should enable the study of a wide range of drugs and their biomarkers in the skin.
Assuntos
Fármacos Dermatológicos/farmacocinética , Derme/metabolismo , Líquido Extracelular/metabolismo , Bombas de Infusão , Microdiálise/instrumentação , Perfusão/instrumentação , Administração Cutânea , Adulto , Biomarcadores/metabolismo , Fármacos Dermatológicos/administração & dosagem , Derme/efeitos dos fármacos , Feminino , Humanos , Masculino , Microdiálise/métodos , Microdiálise/normas , Pessoa de Meia-Idade , Agulhas , Perfusão/métodos , Perfusão/normas , Reprodutibilidade dos Testes , Sódio/metabolismo , Adulto JovemRESUMO
PURPOSE: The purpose of this study is to compare two sampling methods--dermal Open-Flow Microperfusion (dOFM) and dermal Microdialysis (dMD) in an international joint experiment in a single-laboratory setting. We used human ex-vivo skin and sampled topically administered Fentanyl and Benzoic Acid. The second purpose was to provide guidance to researchers in choosing the most efficient method for a given penetrant and give suggestions concerning critical choices for successful dermal sampling. METHODS: The dOFM and dMD techniques are compared in equal set-ups using three probe-types (one dOFM probe and two dMD probe-types) in donor skin (n = 9)--27 probes of each type sampling each penetrant in solutions applied in penetrationchambers glued to the skin surface over a time range of 20 h. RESULTS: Pharmacokinetic results demonstrated concordance between dOFM and dMD sampling technique under the given experimental conditions. The methods each had advantages and limitations in technical, practical and hands-on comparisons. CONCLUSION: When planning a study of cutaneous penetration the advantages and limitations of each probe-type have to be considered in relation to the scientific question posed, the physico-chemical characteristics of the substance of interest, the choice of experimental setting e.g. ex vivo/in vivo and the analytical skills available.