Absorption and Distribution of Naloxone in Rats after Oral and Intravenous Administration

Weinstein, Stephen H.; Pfeffer, Morris; Schor, Joseph M.; Franklin, Larissa; Mintz, Mark; Tutko, E.R.

doi:10.1002/jps.2600620903

Cited by 38 publications

(9 citation statements)

References 9 publications

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“…Such a higher CL int in suspensions was observed for naloxone in at least two of three preparations (Table III). The same observation has been made with hepatocytes from the rat (Blanchard et al, 2004), a species in which naloxone is also a high clearance compound (Weinstein et al, 1973;Mistry & Houston 1987). As the differences between cultures and suspensions do not affect the apparent membrane surface area, this is therefore unlikely to account for the observed differences in the kinetic parameters.…”

Section: Discussionsupporting

confidence: 64%

Comparison of clearance predictions using primary cultures and suspensions of human hepatocytes

Blanchard

Alexandre²,

Abadie

et al. 2005

Xenobiotica

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Various incubation conditions of human hepatocytes were compared for their accuracy in predicting the in vivo hepatic clearance (CL(H)) of model compounds. The test compounds were the highly cleared, low protein bound naloxone (in vivo CL(H) = 25 ml min(-1) kg(-1); free fraction = 0.6), the medium clearance, highly protein bound midazolam (CL(H) = 12 ml min(-1) kg(-1); free fraction = 0.04) and the low clearance, highly protein bound bosentan (CL(H) = 3.9 ml min(-1) kg(-1); free fraction = 0.02). Each compound was tested in three 'hepatocyte systems', using resections from three donors, in the presence and absence of human serum. Those hepatocyte systems were: conventional primary cultures, freshly isolated suspensions and cryopreserved suspended hepatocytes. Except for a twofold overestimated CL(H) for bosentan from conventional primary cultures, and despite variable cryopreservation recoveries, similar predictions of CL(H) were recorded with all hepatocyte systems. Moreover, the CL(H) values obtained with cryopreserved suspended hepatocytes were similar to those obtained with freshly isolated suspensions. For midazolam and bosentan, the predicted in vivo CL(H) was markedly higher in the presence of serum, whereas serum had little influence on the scaled-up CL(H) of naloxone. In vivo, CL(H) was properly approached for naloxone and bosentan (particularly from experiments in the presence of serum), but it was strongly underestimated for midazolam (particularly in the absence of serum). Additional compounds need to be investigated to confirm the above findings as well as to assess why the clearances of some highly protein-bound compounds are still considerably underestimated.

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Section: Discussionsupporting

confidence: 64%

Comparison of clearance predictions using primary cultures and suspensions of human hepatocytes

Blanchard

Alexandre²,

Abadie

et al. 2005

Xenobiotica

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“…This observed value with the BEI method is in fairly good agreement with the half‐life (16 min) in the plasma following i.v. administration to rats based on a two‐compartmental pharmacokinetic model 30. The naloxone concentration in the brain declines parallel to that in the plasma or serum in rats 2, 3.…”

Section: Resulst and Discussionmentioning

confidence: 99%

Blood–brain barrier transport of naloxone does not involve P-glycoprotein-mediated efflux

Suzuki

Miyata

Zaima

et al. 2010

Journal of Pharmaceutical Sciences

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“…However, first-pass liver metabolism of naloxone may be of some importance (Weinstein et al, 1973). This could perhaps explain why s.c. administration is more efficient than i.p.…”

Section: Discussionmentioning

confidence: 99%

Opioids and sexual behavior in the male rabbit: The role of central and peripheral opioid receptors

Ågmo

Paredes

Contreras

1994

J. Neural Transmission

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The purpose of the present series of experiments was to analyze the effects of morphine and naloxone on sexual behavior in the male rabbit, and to evaluate the role of central and peripheral opioid receptors. Morphine was found to inhibit sex behavior in a dose dependent way. The effects were slight at 5 min postinjection. At 1 hr all aspects of sexual behavior were reduced. This effect lasted at least until 3 hrs postinjection. Subcutaneous (s.c.) injection produced effects at lower doses than intraperitoneal (i.p.) injection. Minimal effective doses were 1.25 and 5 mg/kg, respectively. Naloxone also inhibited sexual behavior. Again, s.c. administration had effects at lower doses than i.p. administration (0.25 vs 16 mg/kg). The effects of morphine were reduced but not completely antagonized by several doses of naloxone, independently of whether s.c. or i.p. administration were used. An opioid kappa agonist, bremazocine, inhibited sexual behavior at a low dose (30 micrograms/kg). It is suggested that the inhibitory effects of morphine may be mediated by the kappa receptor. A peripheral opioid antagonist, methylnaloxone, had no effects by itself and was unable to modify the effects of morphine. It is concluded that the effects of morphine are localized within the central nervous system. This is further supported by the observation that loperamide, a peripheral opiate agonist, had only marginal effects on sex behavior.

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Absorption and Distribution of Naloxone in Rats after Oral and Intravenous Administration

Cited by 38 publications

References 9 publications

Comparison of clearance predictions using primary cultures and suspensions of human hepatocytes

Comparison of clearance predictions using primary cultures and suspensions of human hepatocytes

Blood–brain barrier transport of naloxone does not involve P-glycoprotein-mediated efflux

Opioids and sexual behavior in the male rabbit: The role of central and peripheral opioid receptors

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