High-dose pentobarbital pharmacokinetics in hypothermic brain-injured children

Schaible, Deborah H.; Cupit, Gary C.; Swedlow, David B.; Rocci, Mario L.

doi:10.1016/s0022-3476(82)80780-4

Cited by 32 publications

(18 citation statements)

References 18 publications

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“…Cloyd et al [5] have found a log-linear decline in TP serum concentration for his two patients. The results of Schaible et al [ 10] for Ty2 (pentobarbital) were identical to ours (TP).…”

Section: Discussionsupporting

confidence: 89%

“…In our patients, the mean Cl for neonates and children was higher than the pentobarbital one in children treated for Reye syndrome [10], suggesting a potential effect of hepatic dysfunction on pentobarbital metabolism. These patients were also under deep hypothermic condition.…”

Section: Discussioncontrasting

confidence: 48%

“…We have compared our pharmaco kinetic parameters to values previously obtained in adult populations [5,6]. The only information for high-dose barbiturate we have in pediatric population does not concern neonates, but older children for pentobarbital [10]. We have also compared our results to data obtained after single-dose injection of TP (table III).…”

Section: Discussionmentioning

confidence: 99%

“…However, two reports for adults [5,9] found an alteration in the kinetics of elimination, and a biologic half-life which is significantly longer than previously reported values. For hypothermic pediatric patients, Schaible et al [10] showed a decrease of clearance of pentobarbital. We have no knowledge about data for newborns.…”

mentioning

confidence: 99%

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High-Dose Thiopental Pharmacokinetics in Brain-Injured Children and Neonates

Demarquez¹,

Galperine²,

Billeaud³

et al. 1987

Dev Pharmacol Ther

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High-dose thiopental was administered in 8 children with uncontrollable seizures or hypoxic encephalopathy (group A) and 7 full-term neonates with neonatal asphyxia (group B), All of them were submitted to artificial hyperventilation to maintain pCO(2) near 3.5 kPa. Rectal temperature was kept at about 35 °C. Thiopental was infused with a rate of 2-4 mg^-1-kg^-1, with treatment lasting 32-192 h for group A (mean 103 h), and 36-48 h for group B (mean 38.5 h). Plasma concentration-time data were analysed pharmacokinetically. Thiopental elimination half-life was 14.5 h (group A) and 20.9 h (group B). The clearance of thiopental was 0.27 liters × h^-1 -kg"1 (group A) and 0.32 liters × h^-1 × kg-1 (group B). The volume of distribution at steady-state was 5.41 liters-kg 1 (group A) and 8.26 liters-kg-' (group B). These results show that high-dose thiopental pharmacokinetics is not very different for full-term newborns, children and adults. Elimination half-life and volume of distribution are changed when compared to single-dose studies, while clearance is only slightly modified. The time for disappearance of thiopental from blood is also very long (2 to 5 days). These pharmacokinetic characteristics would be worthy of consideration in cases where there may be prolonged use of thiopental, considering the risk of accumulation and toxicity.

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“…Cloyd et al [5] have found a log-linear decline in TP serum concentration for his two patients. The results of Schaible et al [ 10] for Ty2 (pentobarbital) were identical to ours (TP).…”

Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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High-Dose Thiopental Pharmacokinetics in Brain-Injured Children and Neonates

Demarquez¹,

Galperine²,

Billeaud³

et al. 1987

Dev Pharmacol Ther

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“…Hypothermia was correlated with the reduced central volume of distribution of dextromethorphan. During hypothermia, the volume of distribution of many drugs is affected, among which pentobarbital and rocuronium are CYP2D substrates (Schaible et al, 1982;Beaufort et al, 1995). Compared with other P450 isoforms, CYP2D as well as CYP2C can interact with specific functional groups in the substrate binding pocket (e.g., a basic nitrogen for CYP2D6 and an acid for CYP2C9) and help orient them and possibility maintain the metabolic rate and the clearance of the substrates better than other P450 isoforms (Redlich et al, 2008).…”

Section: Zhou Et Almentioning

confidence: 99%

Cardiac Arrest and Therapeutic Hypothermia Decrease Isoform-Specific Cytochrome P450 Drug Metabolism

Zhou¹,

Empey²,

Bies³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Mild therapeutic hypothermia is emerging clinically as a neuroprotection therapy for individuals experiencing cardiac arrest (CA); however, its effects combined with disease pathogenesis on drug disposition and response have not been fully elucidated. We determined the activities of four major hepatic-metabolizing enzymes (CYP3A, CYP2C, CYP2D, and CYP2E) during hypothermia after experimental CA in rats by evaluating the pharmacokinetics of their probe drugs as a function of altered body temperature. Animals were randomized into sham normothermia (37.5-38°C), CA normothermia, sham hypothermia (32.5-33°C), and CA hypothermia groups. Probe drugs (midazolam, diclofenac, dextromethorphan, and chlorzoxazone) were given simultaneously by intravenous bolus after temperature stabilization. Multiple blood samples were collected between 0 and 8 h after drug administration. Pharmacokinetic (PK) analysis was conducted using a noncompartmental approach and population PK modeling. Noncompartmental analysis showed that the clearance of midazolam (CYP3A) in CA hypothermia was reduced from sham normothermia rats (681.6 ؎ 190.0 versus 1268.8 ؎ 348.9 ml ⅐ h ؊1 ⅐ kg ؊1 , p < 0.05). The clearance of chlorzoxazone (CYP2E) in CA hypothermia was also reduced from sham normothermia rats (229.6 ؎ 75.6 versus 561.89 ؎ 215.9 ml ⅐ h ؊1 ⅐ kg ؊1 , p < 0.05). Population PK analysis further demonstrated the decreased clearance of midazolam (CYP3A) was associated with CA injury (p < 0.05). The decreased clearance of chlorzoxazone (CYP2E1) was also associated with CA injury (p < 0.01). Hypothermia was found to be associated with the decreased volume of distribution of midazolam (V 1 ), dextromethorphan (V 1 ), and peripheral compartment for chlorzoxazone (V 2 ) (p < 0.05, p < 0.05, and p < 0.01, respectively). Our data indicate that hypothermia, CA, and their interaction alter cytochrome P450-isoform specific activities in an isoform-specific manner.

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