Evidence of a flip‐flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats

Abstract

The pharmacokinetics of acamprosate were examined in the rat after oral and intravenous administration in order to detect the possible presence of a flip-flop phenomenon. Rats received 9.3 or 73.3 mg/kg of the drug as an intravenous bolus. The same doses were orally administered via gastric intubation. Plasma samples were taken from the jugular vein for determination of acamprosate concentration by liquid scintillation counting. The drug content was also quantified in urine and faeces. The acamprosate bioavailability was close to 20%, the amount recovered in the faeces being around 80% of the administered dose. The terminal slope of the oral plasma curve was significantly lower than that obtained after intravenous administration of the drug at both doses tested (p<2 x 10(-6) in both cases). Moreover, the downward slope after oral administration (lambda2=0.006 +/- 0.001 min(-1)) practically coincided with the first-order absorption rate constant, previously reported by us, obtained using an in situ rat gut technique. It is concluded that the acamprosate absorption rate is considerably slower than its elimination rate so that the drug exhibits flip-flop pharmacokinetics after oral administration. The lower intrinsic first-order absorption rate constant, ka, is responsible for this phenomenon.

Acamprosate modulates experimental autoimmune encephalomyelitis

“…Among factors for the acamprosate's suboptimal efficacy at low doses is the poor intestinal absorption observed in both humans (11%) (Saivin et al 1998) and rodents (20%) (Zornoza et al 2006) as well as considerably faster elimination rate compared to its absorption rate (Zornoza et al 2006). The poor intestinal absorption and the slow absorption rate stem in part from the passive diffusion as being the main route for the intestinal absorption of the drug (Mas-Serrano et al 2000).…”

Pharmacokinetic Behaviors of Orally Administered Drugs

“…This "flip-flop" phenomenon has been observed with multiple drugs; for instance, Zornoza et al (2006) observed it with acamprosate. Acamprosate (calcium bis acetylhomotaurine) is a drug used to prevent relapse in patients with alcohol (ethanol) dependence.…”

“…It can be observed from Fig. 13.8 that acamprosate after IV bolus and oral administration of 9.3 mg/kg follows flip-flop kinetics since the terminal slope in the oral curve is lower than the slope observed in the IV curve (Zornoza et al, 2006). This indicates that the real rate-limiting step is related to acamprosate absorption.…”

Investigation of the relationship between in vitro and in vivo release behaviors of acamprosate from enteric-coated tablets

“…Several studies reported a slow intestinal absorption of acamprosate (Más-Serrano et al, 2000;Zornoza et al, 2002Zornoza et al, , 2004. Zornoza et al (2006) reported that the acamprosate absorption rate is considerably slower than its elimination rate so that the drug exhibits flip-flop pharmacokinetics after oral administration in rats. Therefore, based on its aqueous solubility and intestinal permeability, acamproate is a biopharmaceutics classification system (BCS) Class III drug, as it is highly soluble with low permeability (Amidon et al, 1995).…”

“…In addition, there has been little pharmaceutical research aimed at improving acamprosate bioavailability. Most pharmacokinetic studies were carried out using drug solutions (Más-Serrano et al, 2000;Zornoza et al, 2002Zornoza et al, , 2004Zornoza et al, , 2006Courtyn et al, 2004), and no studies have been reported to date regarding the properties of enteric-coated acamprosate tablets.…”