PHARMACOKINETICS OF THE LONG-ACTING CEFTIOFUR CRYSTALLINE-FREE ACID IN ARABIAN SHE-CAMELS (Camelus dromedarius)

Abstract

Ceftiofur is an important broad-spectrum 3rd generation cephalosporin antibiotic. Owing to its time-dependent antimicrobial actions, the length of time of being above bacterial MIC is the critical point in using ceftiofur for chemotherapy rather than its peak of concentration. Consequently, this experiment was carried out to evaluate, for the first time, the pharmacokinetics of the long-acting ceftiofur crystalline acid-free form (ceftiofur-CAF) in camels. Ceftiofur-CAF 200 mg/ml suspension sterile solution was injected i/m at a dose 6.6 mg/kg. Blood samples were collected from the jugular vein in vacutainer tubes at 0, 0.13, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, and 144 hours after administration of the drug. Ultrahigh Performance Liquid Chromatography-Mass Spectrometry (UPLC MS/MS) was used to measure serum concentration. Pharmacokinetic modeling was by a two-compartment model. Pharmacokinetics of ceftiofur-CAF after single i/m injection in she-camels was best modeled in the two-compartment model, where the drug slowly distributed to a second compartment with poor tissue penetration and high preference to the central compartment. In this study, the maximum plasma concentration (Cmax) was 9.29±0.42 μg/ml at Tmax equals 9.41±1.35 h. The area under the curve (AUC0-∞) was 354.1±57.22 μg/ml*h. The distribution and elimination half-lives were 7.42 and 46.13 h, respectively. The mean residence time (MRT) was 42.01 h. Compared with the rapidly absorbed form of ceftiofur (ceftufor-RAF) in camels, there was almost similar maximal serum concentration but with delayed time to maximal concentration (Tmax), longer means residence time (MRT) and higher distribution and elimination half-lives. In terms of antibacterial efficacy, ceftiofur-CAF stayed above a previously recommended level of 0.2 μg/ml for 7 days, which can be achieved after a single i/m injection of 6.6 mg/kg. The obtained pharmacokinetics data in camels recommends repeated administration of 2 days apart for bacteria requiring MIC levels above 2 μg/ml. Key words: Ceftiofur; pharmacokinetics; camel; cephalosporins FARMAKOKINETIKA DOLGODELUJOČE CEFTIOFURNE KRISTALINIČNE PROSTE KISLINE PRI SAMICAH ARABSKIH KAMEL (Camelus dromedarius) Izvleček: Ceftiofur je pomemben širokospektralni antibiotik 3. generacije cefalosporinov. Zaradi njegovih časovno odvisnih protimikrobnih učinkov je čas, ko je raven ceftiofura nad bakterijskim MIC in ne pri njegovem vrhu koncentracije kritična točka pri uporabi tega antibiotika. Poskus je bil izveden z namenom ovrednotenja farmakokinetike dolgo delujoče ceftiofurjeve kristalinične brezkislinske oblike (ceftiofur-CAF) pri kamelah. Ceftiofur-CAF v koncentraciji 200 mg/ml suspenzije sterilne raztopine smo injicirali i/m v odmerku 6,6 mg/kg. Vzorci krvi so bili zbrani iz vratne vene v vakuumskih epruvetah ob injiciranju antibiotika in nato 8, 15 in 30 minut po injiciranju ter 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 in 144 ur po injiciranju antibiotika. Za merjenje serumske koncentracije je bila uporabljena tekočinska kromatografija ultra visoke ločljivosti (UPLC MS/MS). Farmakokinetično modeliranje je bilo izvedeno z dvokomponentnim modelom. Farmakokinetiko ceftiofur-CAF-a po enkratnem i/m injiciranju v kamele je bilo najbolje modelirati v modelu z dvema predelkoma, kjer se je zdravilo počasi razdeljevalo v drugi predelek s slabo penetracijo v tkiva in veliko prednostjo do osrednjega predelka. Najvišja koncentracija antibiotika v plazmi (Cmax) je bila 9,29 ± 0,42 μg/ml pri Tmax 9,41 ± 1,35 ure. Površina pod krivuljo (AUC0-∞) je bila 354,1 ± 57,22 μg/ml*h. Razpolovni čas razporeditve in izločanja je bil 7,42 oziroma 46,13 ure. Povprečni čas prisotnosti antibiotika (MRT) je bil 42,01 h. V primerjavi s hitro absorbirano obliko ceftiofurja (ceftufor-RAF) pri kamelah je bila skoraj podobna največja koncentracija v serumu, vendar z zakasnjenim časom do največje koncentracije (Tmax), daljšim časom zadrževanja (MRT) in večjim razpolovnim časom porazdelitve in izločanja. Ceftiofur-CAF ostal dni nad predhodno priporočeno ravnijo učinkovitosti 0,2 μg/ml kar 7 dni, kar je bilo mogoče doseči po enkratni i/m injekciji 6,6 mg/kg. Pridobljeni podatki o farmakokinetiki v kamelah priporočajo večkratno dajanje v razmaku 2 dni za bakterije, ki potrebujejo ravni MIC nad 2 μg/ml. Ključne besede: Ceftiofur; farmakokinetika; kamela; cefalosporini