Selective Effect of Adjuvant Arthritis on the Disposition of Propranolol Enantiomers in Rats Detected Using a Stereospecific HPLC Assay

Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 ± 3.0; control, 4.3 ± 1.2). Increased total (S + R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer.     

Delivery and Biodistribution of Traceable Polymeric Micellar Diclofenac in the Rat

The nonsteroidal anti-inflammatory drugs elevate cardiovascular risk, perhaps, due to their accumulation in the heart and kidneys. We designed nanodelivery systems for cardiotoxic diclofenac to reduce its presence in these organs. Diclofenac ethyl ester (DFEE) was encapsulated in traceable micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone) (DFEE-PCL-TM) or poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (DFEE-PBCL-TM). Diclofenac pharmacokinetics and tissue distribution were studied after intravenous (iv) and intraperitoneal administration of the nanoformulations and compared with those after iv doses of free diclofenac (n = 3-6/group). The average diameters for DFEE-PBCL-TM and DFEE-PCL-TM were 37.2 ± 0.06 and 45.1 ± 0.06 nm, respectively. Drug concentration dropped below the assay sensitivity after free drug administration in 6 h, but persisted for 24 h following DFEE-PBCL-TM (2.3 ± 1.4 μg/mL) and DFEE-PCL-TM (1.9 ± 0.6 μg/mL) iv administration. The diclofenac heart:blood and kidney:blood ratios were 5- to 12-fold lower with the nanoformulations than with free diclofenac. Near-infrared fluorescence measurements in tissues suggested exposure patterns to nanocarriers parallel with those achieved for delivered diclofenac by nanoformulations. Administration of DFEE-PCL-TM by iv or intraperitoneal injection, resulted in comparable pharmacokinetics and 6 h postdose near-infrared fluorescence in the heart, kidneys, liver, and spleen. When compared to each other, DFEE-PBCL-TM showed significantly lower diclofenac levels in the heart compared to DFEE-PCL-TM (0.3 ± 0.03 vs. 0.5 ± 0.1 μg/g). Developed nanoformulations of diclofenac prolonged diclofenac circulation and reduced its presence in the heart and kidneys, strongly suggesting cardiac-safe delivery vehicles for diclofenac.     

Pharmacokinetics of meloxicam administered as regular and fast dissolving formulations to the rat: Influence of gastrointestinal dysfunction on the relative bioavailability of two formulations

It is believed that acute pain suppresses nervus vagus, thereby, influencing gastrointestinal secretion and motility, which are the two factors that are necessary for disintegration and dissolution of solid dosage forms. We studied the pharmacokinetics of meloxicam and the effect of vagal suppression on the oral bioavailability and bioequivalence using a marketed (Brand) and a fast dissolving (FD) formulation. In simulated gastric juice, FD was disintegrated in 30 s and released 30% of its meloxicam in 15 min and 60% in 2 h. Brand was disintegrated in 4.5 min with a dissolution rate of 5.6% in 30 min that stayed plateau for the 2 h experiment time. To suppress the vagus nerve, intraperitoneal injection of 20 mg/kg propantheline 1 and 2 h before meloxicam administration was used. Meloxicam (0.9 mg/kg) was administered to both control and vagally suppressed rats i.v. (n = 4–6/group) as well as orally in a paired random fashion as broken pieces of Brand or FD tablets (n = 7/ group). Serial (0–48 h) blood samples were collected for pharmacokinetic and bioavailability studies. Relative bioavailability was measured according to a method in use for bioequivalence assessments. Systemic pharmacokinetics of meloxicam was not affected by vagal suppression. Absolute bioavailability of meloxicam, based on 0–48 h measurement, was >0.68 regardless of the type of formulation and treatment. Vagal suppression, however, significantly reduced AUC_0–24 (μg h mL⁻¹) for Brand (control, 58.8 ± 22.0 vs treated, 22.1 ± 9.7) but not for FD (control, 63.5 ± 17.9 vs treated, 64.6 ± 8.9) indicating a reduced absorption rate for the former. The peak time for Brand was also significantly delayed by over 20 h for Brand and not for FD. Relative bioavailability was confirmed between FD and Brand that were in control but not in the vagally suppressed rats, indicating a disease-dependent bioequivalence. The effect of vagal suppression on the drug absorption rate can be obviated if the disintegration and dissolution become independent of gastrointestinal motility and secretion.     

Dependency of Gastrointestinal Toxicity on Release Rate of Tiaprofenic Acid: A Novel Pharmacokinetic-Pharmacodynamic Model

Purpose. To test the hypothesis that modification of release pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) formulations shifts gastrointestinal (GI) toxicity of the drugs from the upper GI region to the distal intestine. Methods. We assessed tiaprofenic acid (TA)-induced upper and lower increased GI permeability (a surrogate marker of toxicity) after administration of 20 mg and 40 mg/kg regular release (powder) and modified release formulations [sustained release (SR) beads and diethyl--cyclo-dextrin (DCD):TA inclusion complex (INC)]. Urinary excretion of oral doses of GI permeability probes sucrose and ⁵¹Cr-EDTA was determined as measures of gastroduodenal and distal intestine, respectively. Pharmacokinetics of TA enantiomers were also studied following administration of a single 20 mg/kg dose of racemic TA as oral SR beads and iv solution. For powder and INC, previously reported pharmacokinetic data were used. Results. Regular powder significantly increased the permeability at the gastroduodenal level. Modified-release formulations, on the other hand, did not cause damage in the gastroduodenum but produced significant increase in the permeability of the lower intestine. Consequently, to assess the pharmacokinetic-pharmacodynamic relationship, a new model was developed in which contribution of toxicity resulted from direct exposure to the drug was considered. Conclusions. Since the observed site of GI damage corresponds to the site of release and absorption of NSAID from the formulation, the possibility of a shift in the site of damage must be considered for the modified release formulations. A parallel evaluation of upper and lower GI toxicity is essential for a complete assessment of NSAID-induced GI damage.     

Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity

AIM

Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn''s disease (CD), a disease for which the disease severity can be readily ranked.

METHODS

We administered 80 mg verapamil orally to (i) healthy control subjects (n = 9), (ii) patients with clinically quiescent CD (n = 22) and (iii) patients with clinically active CD (n = 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index.

RESULTS

CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r = 0.86, P < 0.0006),

CONCLUSIONS

CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.     

The Effect of Infliximab on Hepatic Cytochrome P450 and Pharmacokinetics of Verapamil in Rats with Pre‐Adjuvant Arthritis: A Drug–Disease and Drug–Drug Interaction

Abstract: Inflammatory conditions result in increased concentration but reduced potency of some cardiovascular drugs. This is associated with increased levels of pro‐inflammatory mediators. Infliximab reduces pro‐inflammatory mediators and reverses the diminishing effect of inflammation on response in the rat. We suggested that infliximab treatment would also reverse the effects of inflammation on drug metabolism and clearance. We examined hepatic cytochrome P450 content and the pharmacokinetics of verapamil in pre‐adjuvant arthritic rats treated with infliximab. Pre‐adjuvant arthritis was induced in male Sprague–Dawley rats with a tail base injection of Mycobacterium butyricum. Animals were monitored for symptoms of arthritis, serum nitrite and C‐reactive protein. On day 6, rats were administered with single s.c. doses of infliximab (10 mg/kg). On day 14, a single i.v. dose of racemic verapamil (2 mg/kg) was administered, and S‐ and R‐verapamil concentrations were determined by high performance liquid chromatography. Hepatic cytochrome P450 content and verapamil protein binding were also measured. Serum nitrite levels were significantly elevated in pre‐adjuvant arthritis. Infliximab did not affect mean nitrite concentrations but there was a significant correlation between nitrite and S‐verapamil concentrations as well as cytochrome P450, CYP3A, and CYP1A contents. Infliximab increased cytochrome P450 enzymes content that had been diminished by pre‐adjuvant arthritis but had no significant effect on verapamil protein binding. Infliximab partially restores hepatic cytochrome P450 enzyme contents. The effect of infliximab on the mean verapamil clearance was not significantly affected due, likely, to the lack of effect on plasma protein binding.     

Antiinflammatory Drug-Induced Small Intestinal Permeability: The Rat Is a Suitable Model

Excretion of orally administrated ⁵¹Cr-EDTA as a marker of small intestinal permeability (a proposed prerequisite for human enteropathy) is increased by corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). We have investigated the suitability of the rat as an animal model of small intestinal permeability using orally administered ⁵¹Cr-EDTA. We dosed Sprague-Dawley rats with NSAIDs and corticosterone followed by ⁵¹Cr-EDTA under conditions reported for humans and measured urinary excretion of the marker. In control rats, the urinary excretion of ⁵¹Cr-EDTA exhibited a skewed-to-the-left frequency distribution curve with a median of 2.13% of the dose. No sex-related differences were noticed in the baseline permeability. In male rats, single therapeutically equivalent doses of indomethacin, flurbiprofen, ibuprofen, naproxen, diclofenac, sulindac, nambumetone, and corticosterone, increased the intestinal permeability by different extents with indomethacin eliciting the maximum effect, and the last four drugs showing minimal potencies. Therapeutically relevant doses of aspirin did not have any significant effect. The increase in permeability was dependent upon the NSAIDs dose. Administration of glucose/citrate, misoprostol and sulfasalazine significantly reduced the effect of indomethacin. Misoprostol antagonized the effect of naproxen but H₂-antagonists and sucralfate did not. All the above observations made in the rat were similar to those previously reported for humans. Thus the rat is a suitable model for studies of small intestinal permeability.     

Stereospecific High-Performance Liquid Chromatographic (HPLC) Assay of Flurbiprofen in Biological Specimens

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