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  • 1
    ISSN: 1573-904X
    Keywords: drug targeting index ; regional administration ; pharmacokinetics ; rat air pouch model ; inflammation ; non-steroidal anti-inflammatory drugs ; diclofenac ; piroxicam ; S[ + ]ibuprofen ; albumin flux
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokinetic parameters of the target and systemic sites, and to compare predictions with observations. Methods. DTI was calculated based on area under the concentration time curve at target (pouch) and systemic site (venous blood) following administration into and sampling from both sites. A model was derived relating DTI to systemic clearance, target permeability, plasma protein binding and fraction of the targeted dose that is systemically available. Results. Both NSAIDs exhibited linear pharmacokinetics over the dose ranges studies. They differed primarily in total body clearance which was approximately 16 fold greater for diclofenac (213 ml hr−l per 250 g) than piroxicam (13 ml hr−l per 250 g). Observed DTIs (11, 114 and 276 for piroxicam, S[ + ]ibuprofen [studied previously] and diclofenac) were ranked in order of total body clearance but were approximately 7.5 fold lower than predicted (101, 700 and 2214 respectively). Conclusions. The discrepancy was explained by the influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammatory response. The originally derived equation for DTI, which assumed only unbound drug diffuses across the target site, was modified to take into account the simultaneous flux of bound drug.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-904X
    Keywords: enoxacin ; ciprofloxacin ; theophylline ; pharmacokinetics ; drug-drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33–46) at steady state plasma concentrations of 0–33 mg · 1−1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg · kg−1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 µM and 16.3 µM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were ‘designed out.’
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-904X
    Keywords: norfloxacin ; theophylline ; pharmacokinetics ; drug–drug interactions ; ciprofloxacin ; enoxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of norfloxacin (NOR), at steady-state plasma concentrations of 0–32 mg · 1−1, on the plasma clearance of a 6 mg · kg-1 iv bolus dose of theophylline (THEO) in the male Sprague-Dawley rat have been studied. The effects were characterised by a Ki value (Ki = 12 µM), which was comparable with Ki values obtained previously under identical conditions for ciprofloxacin, but higher than that obtained for enoxacin. The distributional characteristics, volume of distribution and liver to plasma concentration ratio, were very similar for the three compounds. The only marked pharmacokinetic differences were in hepatic clearance, where there was a rank order NOR 〉 ciprofloxacin 〉 enoxacin, a reverse of the order in the reduction of THEO clearance seen in clinical studies. The advantages of using the steady-state experimental design described here are that equivalent concentrations are utilised to compare related drugs and differences in pharmacokinetics are accounted for, to allow a direct comparison of potency. This information, together with additional pharmacokinetic considerations, suggests that the different effects on THEO clearance seen in the clinic for NOR, ciprofloxacin and enoxacin are not solely due to differences in inhibitory potency, but also involve differences in hepatic clearance and hence systemic availability of the fluoroquinolones.
    Type of Medium: Electronic Resource
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