Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration

Tegeder, Irmgard; Muth-Selbach, Uta; Lötsch, Jörn; Rüsing, Guido; Oelkers, R; Brune, Kay; Meller, Steve; Kelm, Gary R.; Sörgel, Fritz; Geißlinger, Gerd

doi:10.1016/s0009-9236(99)70128-1

Cited by 82 publications

(52 citation statements)

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Section: Methodsmentioning

confidence: 99%

“…The capsules were then removed and excess gel was gently wiped from the skin. Topical application produces a high intradermal concentration of ibuprofen but only a minor fraction (< 1%) enters the plasma or urine (Tegeder et al, 1999).Iontophoresis capsules (internal diameter 10 mm) were placed over the treated sites and skin blood flow was monitored for two minutes from a probe housed within the iontophoresis chamber and another probe 8 mm away from the treated area. A direct current of 350 µA was then passed through 10 mM phenylephrine or a nonspecific conducting medium (0.9% saline) in the iontophoresis chamber for three minutes at the sites pretreated with the ibuprofen or conductive gel.…”

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confidence: 99%

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Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Drummond

2011

Autonomic Neuroscience

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experiments, skin sites were treated with the vasodilator sodium nitroprusside (to counteract vasoconstriction and disperse inflammatory mediators produced during the iontophoresis of phenylephrine); local anaesthetic agent (to determine whether the axon reflex to phenylephrine was neurally-mediated); or the  2 -adrenoceptor agonist clonidine (to investigate the specificity of the adrenergic axon reflex). Phenylephrine evoked marked vasodilatation 8 mm from the site of iontophoresis whereas clonidine and saline-control did not (mean flux increase + S.E. 485 + 132% for phenylephrine; 44 + 24% for clonidine; 39 + 19% for saline-control; p<0.05 for phenylephrine versus control). Axon reflex vasodilatation to phenylephrine was unaffected by variations in blood flow at the site of phenylephrine iontophoresis, but was reduced by ibuprofen pretreatment and abolished by local anaesthetic pretreatment. These findings suggest that prostaglandin synthesis at the site of iontophoresis contributes to but does not account entirely for axon reflex vasodilatation to phenylephrine. Alpha-1 adrenoceptor mediation of axon reflexes could play a role in aberrant sensorysympathetic coupling in neuro-inflammatory diseases.3 Introduction Stimulation of  1 -adrenoceptors generally increases neural discharge in the dorsal horn of the spinal cord whereas  2 -adrenoceptor stimulation is inhibitory (Holden et al., 1999; Pertovaara, 2006). This has implications for pain control, as inhibitory  2 -effects of noradrenaline usually outweigh excitatory  1 -influences on spinal and supra-spinal nociceptive neurotransmission.The effects of -adrenoceptor stimulation on peripheral nociceptive afferents are less clear. In uninjured animals, neither stimulation of the sympathetic chain nor close arterial injection of noradrenaline had any discernable effect on activity of Cfibre nociceptors (Sato and Perl, 1991). Similarly, in humans, sympathetic activity did not affect neural discharge of C-fibre cutaneous nociceptive afferents primed with mustard oil (Elam et al., 1999). Nevertheless, there is evidence that  1 -adrenoceptors influence nociceptive discharge. For example, in uninjured rats blockade of  1 -adrenoceptors inhibited behavioural signs of pain induced by subcutaneous injection of the  1 -adrenoceptor agonist phenylephrine and β-methylene-ATP (an agonist for purinergic P2X3 receptors) (Meisner et al., 2007), whereas blockade of  2 -adrenoceptors was ineffective. Similarly, blockade of  1 -but not  2 -adrenoceptors abolished hyperalgesia and C-fibre discharge evoked by intradermal injection of capsaicin (Kinnman and Levine;1995;Ren et al., 2005). In studies on healthy humans, intradermal injection of  1 -and  2 -adrenergic agonists increased sensitivity to heat-pain (Fuchs et al., 2001), as did iontophoresis of noradrenaline and phenylephrine in mildly burnt or inflamed skin (Drummond, 1995;Drummond, 1998;Drummond, 2009a).Animal studies have shown that  1 -adrenoceptors may also influence the flare that develops around the sit...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Drummond

2011

Autonomic Neuroscience

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“…Another area of development is the use of microdialysis for cutaneous bioavailability of drugs that has not come too far in spite of promising results (93)(94)(95)(96). In comparison to blister techniques, it can be said to be very sophisticated, although still being limited by adsorption phenomena.…”

Section: Development Of Microdialysis and Alternativesmentioning

confidence: 99%

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Hammarlund‐Udenaes

2017

AAPS J

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Abstract.Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

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“…The flurbiprofen concentrations in the subcutaneous fat, tendon, muscle and periosteal tissues were significantly higher (P = 0.0009, 0.0018, 0.0026 and 0.0012, respectively) in the patients receiving topically applied flurbiprofen ( To show the remarkable differences between the topical application and the oral administration, we calculated the tissue : plasma concentration ratio (T : P ratio), which was defined as a ratio of the tissue concentration divided by the plasma concentration. The T : P ratio in the patients receiving orally administered flurbiprofen averaged 6% (95% CI 1, 10) for the fat, 7% (95% CI 3, 12) for the tendon, 3% (95% CI 1, 4) for the muscle, 9% (95% CI 3,16) for the periosteum and 4% (95% CI 1, 8) for the bone. On the other hand, the T : P ratio in the patients receiving topically applied flurbiprofen averaged 173% (95% CI 20, 326) for the fat, 160% (95% CI 35, 285) for the tendon, 77% (95% CI 27, 126) for the muscle, 65 % (95% CI 24, 105) for the periosteum and 11 % (95% CI -2, 24) for the bone.…”

Section: Resultsmentioning

confidence: 98%

“…To evaluate the efficacy of a topical application, it is an important strategy to compare a tissue concentration of a certain NSAID between the topical application and the oral administration.However, only a few studies have been conducted to evaluate such efficacy to date. Tegeder et al [3] compared the concentration of ibuprofen in the muscle and fat tissues between topical application and oral administration. Recently, we performed a randomized pharmacokinetic study to compare the concentrations of diclofenac in muscle, synovium and fat tissues between topical application and oral administration according to the regulatory approved dosing guidelines [4].…”

Section: Introductionmentioning

confidence: 99%

Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

Kai

Kondo

Kawaguchi

et al. 2013

Brit J Clinical Pharma

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AIMTo compare tissue concentrations of flurbiprofen resulting from topical application and oral administration according to the regulatory approved dosing guidelines. METHODSixteen patients were included in this study. Each patient was randomly assigned to the topical application or oral administration group. In each group, a pair of tapes or a tablet, containing a total of 40 mg flurbiprofen, was administered twice at 16 and 2 h before the surgery. RESULTSThe flurbiprofen concentration in the fat, tendon, muscle and periosteum tissues was significantly higher (P < 0.0330) after topical application (992 ng CONCLUSIONTopical application is an effective method to deliver flurbiprofen to the human body, particularly to soft tissues near the body surface.

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Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration

Cited by 82 publications

References 57 publications

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

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