Markus Müller

Application of microdialysis to clinical pharmacokinetics in humans

Measurement of drug concentrations in tissues would be useful for clinical pharmacokinetic studies, but appropriate experimental methods are not available at present. The aim of this study was to assess the scope and limitations of the microdialysis technique for human tissue pharmacokinetic studies.

Simultaneous determination of levofloxacin and ciprofloxacin in microdialysates and plasma by high-performance liquid chromatography

The fluoroquinolones levofloxacin and ciprofloxacin were simultaneously determined in microdialysis and plasma samples by reversed-phase high-performance liquid chromatography (HPLC) and fluorescence detection. After a simple sample preparation step the analytes were separated in the isocratic mode within 12 min. The calibration curve for levofloxacin was linear from 0.0156 to 5 gm l −1 and 0.02–12.5 gm l −1 in microdialysates and plasma samples, respectively. The limits of quantification for levofloxacin and ciprofloxacin were 0.0156 and 0.1 gm l −1 in microdialysis samples, and 0.02 and 0.1 gm l −1 in plasma samples, respectively. Some experimental details concerning microdialysate dilution and plasma protein precipitation were described to ensure accurate quantitation. The assay can be used as a routine method to analyse microdialysis and plasma samples from clinical studies.

Diclofenac concentrations in defined tissue layers after topical administration

To date it is unclear whether therapeutic concentrations are attained in target tissues after topical administration of nonsteroidal anti‐inflammatory drugs. Therefore this study in healthy volunteers was undertaken to measure diclofenac concentrations attained in defined tissue layers directly underlying the site of topical diclofenac application by in vivo microdialysis.

In vivo characterization of transdermal drug transport by microdialysis

Abstract The aim of the present study was to evaluate the scope and limitations of the microdialysis technique as a tool for pharmacokinetic studies of transdermal therapy systems (TTS) and for characterization of the transdermal diffusion process in man. Nicotine (TTS; 21 mg/24 h) or estradiol (TTS; 100 μg/24 h) were administered transdermally to 15 healthy volunteers. Microdialysis probes were inserted into defined skin layers directly underlying the TTS. Calibration of the probes was carried out in vitro and in vivo. The position of the probe and the depth of probe tip were established by 2D ultrasound scanning. Complete concentration versus time profiles could be obtained for nicotine. There was a high degree of association between the position of the microdialysis probe, measured in mm from the skin surface, and the area under the nicotine concentration versus time curve (AUC) or the steady state concentration in skin layers. Microdialysis measurements were reproducible for nicotine. Estradiol, which is poorly water soluble, was non-dialysable. Microdialysis sampling can provide previously inaccessible information about the transdermal diffusion process of select drugs and therefore represents a valuable addition to traditional attempts for characterization of the transdermal drug transport and of TTS release kinetics.

Gastrointestinal transit and release of 5‐aminosalicylic acid from 153Sm‐labelled mesalazine pellets vs. tablets in male healthy volunteers

Background :u2002Mesalazine (5‐aminosalicylic acid)‐containing formulations, designed to optimize drug delivery to the ileo‐caecal region, represent a cornerstone in the treatment of inflammatory bowel diseases.

Microdialysis: an in vivo approach for measuring drug delivery in oncology

Abstract. Microdialysis (MD) is a catheter-based sampling method that provides the opportunity to directly study tumor drug exposure and metabolism in a minimally invasive way. Tumor drug exposure, which is directly linked to clinical outcome, may be substantially reduced due to diffusion barriers in solid tumors. Therefore plasma drug profiles are frequently inappropriate for predicting outcome in oncology. This contribution focuses on the application of MD in preclinical and clinical oncological research and presents an overview of the current literature. It is concluded that MD, in combination with pharmacokinetic/pharmacodynamic modeling, has the potential to contribute to the design of optimal treatment schedules and to select appropriate drug candidates, doses, and dosing intervals for established and new anticancer drugs.

Transcapillary insulin transfer in human skeletal muscle

Background Transcapillary insulin transfer is considered a rate‐limiting step in insulin action at supraphysiological insulin concentrations. However, it remains unclear whether this concept also applies for physiological conditions.

Paracrine effects of angiotensin-converting-enzyme- and angiotensin-II-receptor- inhibition on transcapillary glucose transport in humans.

The paracrine renin-angiotensin-system (RAS) is increasingly recognized to play an important role in the regulation of both, regional vascular tone and regional glucose metabolism. To date, however, a selective investigation of paracrine RAS effects in an in vivo clinical setting was beyond technical reach. We here set out to selectively study the metabolic effects of paracrine RAS inhibition at different levels in healthy volunteers (n = 8). For this purpose bradykinin, enalaprilate and losartan were administered locally to the interstitial space fluid in skeletal muscle by means of reverse microdialysis and transcapillary glucose transport was measured simultaneously. During reverse microdialysis with bradykinin and enalaprilate a significant decrease in arterial-interstitial-gradient for glucose (AIG(glu)) was observed (from 1.49 +/- 0.08 mM to 0.12 +/- 0.63 mM (p = 0.018) for bradykinin and from 1.5 +/- 0.07 mM to 0.24 +/- 0.67 mM (p = 0.043) for enalaprilate). In contrast, losartan had no effect on AIG(glu). The changes in transcapillary glucose transport during bradykinin and enalaprilate administration were accompanied by significant increases in interstitial lactate levels which was most pronounced for bradykinin (from 0.14 +/- 0.01 mM to 0.40 +/- 0.07 mM, p = 0.018). We conclude that paracrine angiotensin-converting-enzyme (ACE) inhibition but not angiotensin II (AT-II) receptor blockade decreases AIG(glu) and facilitates transcapillary glucose transport due to an increase in interstitial bradykinin concentration. These results support the concept that blood pressure control with ACE-inhibitors but not with AT-II-receptor-antagonists has beneficial long term metabolic consequences in hypertensive, hyperinsulinemic subjects.

Comparison of three different experimental methods for the assessment of peripheral compartment pharmacokinetics in humans

In many cases the concentration reached in a peripheral effect compartment rather than in plasma determines the clinical outcome of therapy. Therefore, several experimental approaches have been developed for direct assessment of drug kinetics in peripheral compartments. Particularly saliva sampling, skin blister fluid sampling, and in vivo microdialysis are frequently employed for measuring peripheral drug concentrations. However, data derived from these techniques have never been directly compared. In the present study, the tissue kinetics of theophylline were measured following single dose administration simultaneously in cantharides induced skin blisters, saliva and microdialysates of subcutaneous- and skeletal muscle- tissue and compared to plasma concentrations. Theophylline was administered to 9 healthy volunteers as an i.v. infusion of 240 mg. Mean ratio (AUCsaliva/AUCplasma) was 0.63 +/- 0.05, mean ratio (AUCblister/AUCplasma) was 0.69 +/- 0.12, mean ratio (AUCmuscle/AUCplasma) was 0.41 +/- 0.10, mean ratio (AUCsubcutaneous/AUCplasma) was 0.34 +/- 0.07. The time course of the concentration(peripheral)/concentration(plasma)-ratios showed that tissue concentrations obtained by microdialysis were closely correlated to free plasma levels, whereas saliva- and cantharides blister data overestimated the corresponding free plasma concentrations. It is concluded that microdialysis represents a reliable technique for the measurement of unbound peripheral compartment concentrations and is superior to saliva- and skin blister concentration measurements.

Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors

BACKGROUNDnRodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed.nnnMETHODSnIn this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs).nnnRESULTSnUsing microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors.nnnCONCLUSIONSnThe tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.