Comparative Pharmacokinetics and Metabolisms of Caffeine in Sheep Breeds

Abstract

ABSTRACT. The purpose of this study was to investigate the effect of breed on the pharmacokinetics and metabolism of caffeine (CF) and the hepatic metabolic capacity in sheep. CF was administered as a single intravenous dose of 5 mg/kg b.w. in Morkaraman (MK), Akkaraman (AK) and Anatolia Merino (AM) sheep breeds. The plasma levels of CF and its primary metabolites, theobromine (TB), paraxanthine (PX) and theophylline (TP), were measured using high-performance liquid chromatography. Pharmacokinetic parameters of CF and its metabolites were calculated. Plasma TB+PX+TP/CF metabolic ratio was determined as an alternative to CF clearance for the determination of hepatic metabolic capacity. In the three breeds, all kinetic parameters of CF differed significantly (P<0.05) except for volume of distribution. Elimination of CF was slow in the MK (Cl T ; 0.03  0.01 l hr/kg, t 1/2z ; 15.74  7.35 hr) and AM (Cl T ; 0.05  0.02 l hr/kg, t 1/2z ; 9.68  5.21 hr) breeds when compared with the AK breed (Cl T ; 0.08  0.01 l hr/kg, t 1/2z ; 6.84  0.79 hr). There was significant correlation (r 2 =0.904, P<0.01) between CF clearance and the plasma TB+PX+TP/CF ratio calculated at 7 hr after CF administration. The plasma TB+PX+TP/CF ratios were statistically different (P<0.05) among the breeds (MK, 0.155  0.062; AK, 0.468  0.107; AM, 0.254  0.099). These results suggest that the pattern of drug biotransformation should be consistently tested for all breeds within species. Further studies are needed to determine the biochemical and molecular events underlying such an effect. The activities of biotransformation enzymes affect either the pharmacological or toxicological impacts of drugs and xenobiotics. During the past decades, much of the detailed knowledge of enzymes responsible for biotransformation has been learned in laboratory animals and humans. In contrast, knowledge of biotransformation enzymes and various factors (breed, age) causing their variability in veterinary food-producing species is still incomplete [10,12,15,19,26,35].Genotyping and phenotyping are the 2 methods that are used today to assess the in vivo activity of biotransformation enzymes. However, the optimal method of describing actual enzyme activity is phenotyping because it is a reflection of the combined effects of genetic, environmental and endogenous factors on enzyme activity [25]. Phenotyping for drug metabolizing enzymes is defined as measuring its actual in vivo activity in an individual. This is performed by administrations of probe substrates for various isoforms of cytochrome P450 (CYP 450) and other enzymes and subsequent determination of appropriate pharmacokinetic parameters or is performed by using metabolism [12].Caffeine (CF) is now widely used to assess genetic, environmental and race/breed differences for some enzymes and the hepatic metabolic capacity (total activity of enzymes metabolizing CF) because of its pharmacokinetics and almost complete biotransformation by some CYP 450 enzymes in liver [17,23]. The primary metabolic pathway...

Caffeine alters oxidative homeostasis in the body of BALB/c mice

“…The signifi cant effect of caffeine on oxidative balance is a little surprising in the animals one and two days after caffeine application. Caffeine easily cross barriers in the body and is eliminated with half time up to 10 hours (28). Beside the elimination, it is metabolized by CYP1A2 (29,30).…”

Measurements of caffeine and plasma metabolite/caffeine ratios as a test for hepatic drug-oxidizing capacity in goats

“…Plasma concentrations of CF and its metabolites were measured using the HPLC method previously reported by Christensen et al (2003), with minor modifications (Uney and Traş, 2011). The HPLC system consisted of a SRVYR-PDA5 detector system, a SRVYR-AS autosampler and a SRVYR-Lpump LC pump (Thermo Electron Corporation, Finnigan Surveyor, England).…”

“…The hepatic drug-oxidizing capacity in humans can be determined by calculating various pharmacokinetic parameters including the area under the plasma concentration-time curve (AUC), total body clearance (Cl tot ) and half-life of elimination (t 1/2β ) of CF (Rostami-Hodjegan et al, 1996;Zaigler et al, 2000;Jodynis-Liebert et al, 2004;Tarantino, 2009). Plasma clearance of CF has been used to evaluate the hepatic drug-oxidizing capacity in monkeys, rabbits, rats and mice (Bonati et al, 1984), dogs (Golden et al, 1994), horses (Aramaki et al, 1995;Peck et al, 1997), donkeys (Peck et al, 1997), cattle (Janus and Antoszek, 2000;Janus et al, 2001), sheep (Danielson and Golsteyn, 1996;Uney and Traş, 2011), pigs (Monshouwer et al, 1995) and camels (Wasfi et al, 2000).…”

“…However, quantitative differences in CF metabolism exist among animal species. It has been determined that CF is predominantly metabolized to TP in sheep (Danielson and Golsteyn, 1996;Uney and Traş, 2011), horses and donkeys (Peck et al, 1997), camels (Wasfi et al, 2000), dogs (Boothe et al, 1994) and monkeys (Bonati et al, 1984;Berthou et al, 1992), whereas it is predominantly metabolized to PX in cattle (Danielson and Golsteyn, 1996).…”

“…The pharmacokinetics and demethylation of CF have been studied in several species, including horses (Schumacher et al, 1994;Peck et al, 1997), donkeys (Peck et al, 1997), cattle (Danielson and Golsteyn, 1996;Janus and Antoszek, 2000) and sheep (Danielson and Golsteyn, 1996;Uney and Traş, 2011). Zweers-Zeilmaker et al (1996) have determined the in vitro demethylation and in vivo clearance of CF in dwarf goats.…”