Chronopharmacological Study of Cephalexin in Dogs

Abstract

Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first-generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration-time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83+/-3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10:00 and 22:00 h, with a two-week interval of time between the two clock-time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52+/-2.7 vs. 18.77+/-2.8 microg/mL) administration. The elimination half-life was prolonged 1.5-fold after the 22:00 h compared to the 10:00 h administration (2.69+/-0.9 vs. 1.79+/-0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration-time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 microg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10:00 and 22:00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single-dose study require confirmation by future steady-state, multiple-dose studies. If such studies are confirmatory, no administration-time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.

Chronopharmacokinetics of Imipenem in the Rat

“…Boulamery et al 966 circadian-time dependent in rodents (Pons et al, 1996). These data agree with previously reported higher values of renal clearance for gentamicin, amikacin, tobramycin, and ampicillin in rodents (Lin et al, 1994;MesnardRici & White, 1998;Rao et al, 1997;Rebuelto et al, 2003aRebuelto et al, , 2003bWhite et al, 1995;Yoshiyama et al, 1993) and cephalexin in dogs (Prados et al, 2007) during the nocturnal activity span.…”

“…Some studies have reported circadian rhythm dependencies in the pharmacokinetics of certain antimicrobial agents (gentamicin, tobramicin, ampicillin, isepamicin, amphotericin B, cephalexin, cephtriaxone, and norfloxacin) in the rat, dogs, or man (Lin et al, 1994;Mesnard-Rici & White, 1998;Prados et al, 2007;Rao et al, 1997;Rebuelto et al, 2003aRebuelto et al, , 2003bWhite et al, 1995;Yoshiyama et al, 1993), but the present work is the first one demonstrating chronopharmacokinetic changes in a betalactam antibiotic agent (i.e., imipenem).…”

Chronokinetic study of cefalexin in postprandial and fasting volunteers

“…C max was higher after the daytime administration and decreased significantly by 19% in night-time administration, and is in good agreement with the reported cephalexin chronokinetics in dogs (Prados et al 2007). Similarly, the rats administered oral ceftibuten, another b-lactam antibiotic substrate of PEPT1, at 20:00 h showed greater C max than rats administered this medication at 08:00 h (Pan et al 2003).…”

“…43, No. 5, October 2012 identified that b-lactam antibiotics (cephalexin) pharmacokinetics varies with time of administration in fasted dogs (Prados et al 2007). Nevertheless, there seems to be little understanding about the chronokinetics of b-lactam antibiotics in human.…”

Do Restless Legs Syndrome (RLS) and Periodic Limb Movements of Sleep (PLMS) Play a Role in Nocturnal Hypertension and Increased Cardiovascular Risk of Renally Impaired Patients?

“…Chronomedicine is the study of the chronobiology of health and disease and the translation of applicable findings to clinical medicine (Portaluppi, 2007). In the past few years, in particular, a chronobiological approach has been extensively used in medical research, leading to a better understanding of the pathophysiological mechanisms and features of many medical conditions and public health problems (Burioka et al, 2008;Colognesi et al, 2007;Kawahara et al, 2008;Lee et al, 2008;Leibowitz et al, 2007;Leiza et al, 2007;Lin et al, 2008;Mbanu et al, 2007;Ohkura et al, 2007;Perez-Lloret et al, 2008;Sadick et al, 2007;Sallinen et al, 2008;Shah et al, 2007;Tsai et al, 2007) as well as greater insight of therapeutic issues (Boulamery et al, 2007;Bruguerolle, 2008;Coudert et al, 2008;Dispersyn et al, 2008;Dridi et al, 2008;Hermida, 2007;Hermida et al, 2007bHermida et al, , 2008Prados et al, 2007;Smolensky et al, 2007;Tsuruoka et al, 2008).…”