Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations

Abstract

Arthropathia in juvenile animals is the most important toxic effect induced by quinolones. We conducted pharmacokinetic and morphological studies with ofloxacin on non-human primates (Callithrix jacchus, Marmosets) and rats. In the marmoset, electron microscopy and the application of immuno-morphological methods proved to be suitable for the detection of specific alterations in cartilage (e.g. loss of proteoglycans and altered chondrocytes). Subsequently performed electron microscopic examinations in rats showed similar specific alterations of the femur cartilage surface after multiple oral applications of 600 mg ofloxacin/kg body wt. These results were correlated with pharmacokinetic data obtained for the same species. After single oral application of 100, 300 or 600 mg ofloxacin/kg body wt to 5 week-old rats peak plasma levels were achieved 15-45 min after administration indicating a rapid absorption of the drug. The following peak concentrations were measured for the three doses applied (mean +/- SD): 8.9 +/- 2.1, 22.6 +/- 7.5 mg/l and 33.5 +/- 9.8 mg/l, respectively. After 360 min the concentrations were 1.1 +/- 0.4, 5.9 +/- 2.5 and 15.9 +/- 5.1 mg/l, respectively. After subcutaneous injection of 100 mg ofloxacin/kg body wt the mean peak concentration was 27.7 +/- 2.6 mg/l after 45 min (0.5 +/- 0.2 mg/l after 360 min). In the marmoset higher plasma concentrations were measured with comparable doses. One, 3, and 6 h after the last of nine administrations of 200 mg ofloxacin/kg body wt, the mean (+/- SD) plasma concentrations were: 42.7 +/- 16.7, 40.6 +/- 9.5, and 26.5 +/- 3.6 mg ofloxacin/l plasma. Typical alterations of the joint cartilage of juvenile rats (e.g. opened chondrocyte cavities, swelling of rough endoplasmic reticulum and mitochondrial swelling in the chondrocytes) were induced by oral administration of ofloxacin at doses that were approximately 100 times higher than therapeutic ones, but led to peak plasma concentrations which were only approximately 10 times above the therapeutic level.

Diagnosis of Quinolone-induced Arthropathy in Juvenile Dogs by Use of Magnetic Resonance(MR) Imaging.

“…3). These macro-and micropathological findings were in agreement with previous results of known quinolones in immature dogs [1,3,7,11], and basically resembled those reported in multiple species such as rats [4], rabbits [2], non-human primates [9] and others [5,6], although there were slight differences in the arthropathic dose among the quinolones. Unfortunately, the sensitivity of MR imaging for the detection of vesicular lesions in articular cartilage remains an unresolved issue, as Gough et al [2] reported.…”

Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

“…Increase of fibronectin staining in articular cartilage has been identified as a very sensitive indicator and early reaction after quinolone treatment in immature rats and marmosets (12,25). F6rster et al (12) (23,24).…”

“…Immunohistochemical studies of articular cartilages from growing rats and marmosets dosed with ofloxacin revealed treatment-related changes in antigen expression within chondrocytes and extracellular matrix (12,25). In cartilage from marmosets that had received ofloxacin for 5 days, an increase in fibronectin staining was observed in matrix adjacent to fissures and in some areas without fissures (25). In cartilage from rats that had been dosed with ofloxacin, a similar increase of fibronectin and a reduced expression of various integrins (e.g., the fibronectin receptor avr3¡) on chondrocytes was detected (12 (Fig.…”

A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Ofloxacin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs.

“…63(8): 867-872, 2001 New quinolone antimicrobial agents (quinolones) are widely used in clinical fields because of their broad spectra and bactericidal activity. However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4, 9, 10], rabbits [11], dogs [3, 5, 8, 20], nonhuman primates [17] and others [1, 2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].…”

“…However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4,9,10], rabbits [11], dogs [3,5,8,20], nonhuman primates [17] and others [1,2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].…”