Plasma terminal half‐life

Toutain, Pierre‐Louis; Bousquet‐mélou, Alain

doi:10.1111/j.1365-2885.2004.00600.x

Cited by 270 publications

(234 citation statements)

References 10 publications

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“…In such a situation, the terminal slope is no longer controlled by the clearance and volume of distribution but instead by the bioavailability factors (rate and also extent of absorption). Likewise, recognizing the existence of flip-flop avoids incorrect calculation of some parameters [21].…”

Section: Discussionmentioning

confidence: 99%

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

Zornoza

Cano-Cebrián

Hipólito

et al. 2006

Biopharm & Drug Disp

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zornoza

Cano-Cebrián

Hipólito

et al. 2006

Biopharm & Drug Disp

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“…The lowered exposure by oral administration observed in humans is also achieved with little change in t 1/2 (Xiong et al, 2004;Sessa et al, 2006). A possible explanation for the unchanged t 1/2 is that the observed t 1/2 after the second dose reflects the absorption rate rather than the elimination rate (i.e., flip-flop kinetics; Toutain and Bousquet-Mélou, 2004). Such kinetics is supported by the results showing that the intravenous t 1/2 with the prior oral administration was 3ϳ4-fold shorter than the oral t 1/2 .…”

Section: Discussionmentioning

confidence: 99%

Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats

Kitamura

Yamamoto²,

Nagayama³

et al. 2007

Drug Metab Dispos

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ABSTRACT:TSU-68 ((Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) is a new drug under investigation that inhibits receptor tyrosine kinases involved in tumor angiogenesis. In clinical pharmacokinetic studies, lower plasma concentrations of orally administered TSU-68 are observed after the second dose given within 12 h after the first dose. We examined the cause of this observation through in vivo and ex vivo approaches using rats in which a rapid decrease in the exposure was shown as in humans. In rats, the area under the concentration-time curve after the second dose was decreased to 26% of that after the first dose during administration of TSU-68 (200 mg/kg) twice a day. Plasma clearance of TSU-68 intravenously administered 12 h after oral administration was 1.5-fold higher and the half-life was 2-fold shorter compared with those after the single intravenous administration. The amount of absorbed TSU-68, as indicated by the radioactivity totally excreted in the bile and urine following oral administration of [ 14 C]TSU-68, was unchanged by the prior oral administration. These results demonstrate that administered TSU-68 causes an increase in its elimination but not a decrease in its absorption after the subsequent administration. Furthermore, rat liver taken 12 h after administration of TSU-68 exhibited 6-fold higher activity of its microsomal oxidase than untreated liver. This result suggests that TSU-68 induced its own oxidative metabolism (i.e., autoinduction). In conclusion, the decrease in plasma concentrations of TSU-68 during the administration twice a day to rats was due to the rapid autoinduction. The same mechanism is probably at work in the clinical setting.

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“…The longer half-life observed following oral administration is consistent with the flip-flop effect [97] and has not previously been described for omeprazole in the horse. The flip-flop effect primarily occurs in drugs that have a short half-life following intravenous administration.…”

Section: Discussionsupporting

confidence: 68%

“…The flip-flop effect primarily occurs in drugs that have a short half-life following intravenous administration. It occurs when the rate of absorption following extra-vascular administration becomes the predominant determinant of plasma concentrations, rather than the rate of elimination, as ongoing absorption of the drug interferes with the calculation of clearance and determination of half-life [97]. As such, the reported half-life following extra-vascular, in this case oral, should not be misinterpreted as a measure of drug clearance [97].…”

Section: Discussionmentioning

confidence: 99%

Factors affecting the pharmacokinetics and pharmacodynamics of omeprazole in the horse

Sykes¹

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Equine Gastric Ulcer Syndrome (EGUS) is a common condition of the horse, affecting a broad range of horse usages and types. Recently the terminology of the syndrome has been expanded to include terms Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD) to describe diseases of the squamous and glandular mucosa of the stomach, respectively. Omeprazole, a proton pump inhibitor that blocks acid production, is considered the treatment of choice for EGUS and it has been widely used for this purpose for nearly 20 years. Yet, surprisingly, despite its widespread use little is known about the factors that affect its efficacy, such as the impact of formulation, diet and dose. Further, although it is commonly believed that the once daily administration of omeprazole results in durations of acid suppression exceeding 24 hours, there is conflict in the literature as to the validity of this belief. Recent clinical studies have demonstrated that the healing rate for EGGD is inferior to that of ESGD, raising further questions as to the efficacy of omeprazole under clinically relevant conditions. One potential reason for this observation is that the duration of intra-day acid suppression required for healing of ESGD may be less than that for EGGD. This, coupled with the possibility that once daily administration of omeprazole may not result in acid suppression for the entire 24 hour treatment interval, provides a potential explanation for the poor EGGD healing rates that have been recently reported. The purpose of this thesis was to investigate the factors that affect the efficacy of omeprazole in the horse. The studies were conducted in four parts; firstly, the effect of formulation and diet on the pharmacokinetics of omeprazole were investigated; secondly, a model that allows continuous intra-gastric pH measurement under clinically relevant conditions was developed; thirdly, the impact of diet and dose on the pharmacokinetics and pharmacodynamics of omeprazole were investigated; and lastly, the relationships between key pharmacokinetic and pharmacodynamic variables were investigated. The findings of the study suggested that some method of physical protection is required to protect the omeprazole from degradation in the acidic environment of the stomach and to improve bioavailability. However, significant differences were not present between formulations utilising the two most common forms of protection, namely the use of enteric coated granules in paste or buffering of the formulation. This suggests that the method of protection, buffering of the formulation or the use enteric coated granules in paste, used is less important than protection per se. The earlier studies of the thesis 3 suggested that an effect of feeding may be present on the pharmacokinetics of omeprazole but a statistically significant effect could not be demonstrated. Similarly, the latter studies suggested that diet may play a role in bioavailability with ad libitum roughage diets impairing absorption, but no statistically signi...

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Plasma terminal half‐life

Cited by 270 publications

References 10 publications

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

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

Decrease in Plasma Concentrations of Antiangiogenic Agent TSU-68 ((Z)-5-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid) during Oral Administration Twice a Day to Rats

Factors affecting the pharmacokinetics and pharmacodynamics of omeprazole in the horse

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