The use of nonhuman primates in the study of bilirubin metabolism and bile secretion

Cornelius, Charles E.

doi:10.1002/ajp.1350020403

Cited by 8 publications

(4 citation statements)

References 59 publications

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“…However, since there is no clear evidence that post-parturition hyperbilirubinaemia occurs in rats, the ability of Zn-protoporphyrin to prevent physiological jaundice in an appropriate animal model, such as primates, remains to be elucidated. The non-human primate is recognized as the best animal model for many specific investigations of human diseases, including bilirubin metabolism (Cornelius, 1982).…”

mentioning

confidence: 99%

Prevention of neonatal hyperbilirubinaemia in non-human primates by Zn-protoporphyrin

Qato¹,

Maines²

1985

Biochemical Journal

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Non-human primates were used as a model of human neonatal hyperbilirubinaemia and its chemotherapeutic suppression. High levels of haem oxygenase activity were detected in the liver and the spleen of neonatal rhesus (Macaca mulatta) and cynomolgus (Macaca irus) monkeys. When 1-day-old neonatal animals were given a single injection of Zn-protoporphyrin (40 mumol/kg, subcutaneously), serum bilirubin levels declined to nearly normal adult levels within 24 h and remained suppressed throughout the postnatal period (12 days). This treatment inhibited the activities of haem oxygenase and biliverdin reductase in the liver and the spleen, without affecting that of the brain. Zn-protoporphyrin treatment did not alter the activity of brain biliverdin reductase or increase brain bilirubin levels. The biological disposition of Zn-protoporphyrin was examined by measuring the biliary and urinary excretion of the metalloporphyrin complex, as well as its uptake and deposition in blood cells and tissues. Biliary excretion of the metalloporphyrin was minimal (0.12% over a 28 h period), and no evidence was detected for the urinary excretion of Zn-protoporphyrin. However, the concentration of metalloporphyrin in erythrocytes increased over the duration of the experiment (11 days) to such an extent that 46% of the administered compound was taken up by the cells. It appeared that the molecular basis for the sustained suppression of haem oxygenase activity and bilirubin production by Zn-protoporphyrin involved the release of the metalloporphyrin in the normal process of the degradation of fetal erythrocytes. The scope of the biological activity of Zn-protoporphyrin to alter haem-dependent processes appeared limited in nature, insofar as the microsomal contents of cytochrome P-450 and b5, as well as the aniline hydroxylase, were similar to those of the control animals. Also, the concentration of glutathione in the liver was unchanged. These findings suggest the potential usefulness of Zn-protoporphyrin in experimental and perhaps clinical conditions in which hyperbilirubinaemia occurs.

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confidence: 99%

Prevention of neonatal hyperbilirubinaemia in non-human primates by Zn-protoporphyrin

Qato¹,

Maines²

1985

Biochemical Journal

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“…Baboons are close to humans in terms of phylogeny and longer gestational period (184 ± 2 days). Like human neonates, newborn primates exhibit hyperbilirubinemia, intracellular conjugation, and excretion of pigments into bile [10]. The newborn baboons are relatively big in size (0.9-1.0 kg at term gestation), and can be stud ied for long periods.…”

Section: Discussionmentioning

confidence: 99%

Bile Flow and Composition in Preterm, Term and Infant Baboons

Bhat

Chari²,

Meller³

et al. 1997

Neonatology

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We studied the maturational changes in bile composition, bile flow and choleretic effects of sodium taurocholate and secretin in preterm (160 ± 2 days, n = 4, group I), term (184 ± 2 days, n = 4, group II), 7-day postnatal age (n = 5, group III) and 60-day-old (n = 5, group IV) baboons. The canalicular bile flow was determined by ¹⁴C-erythritol clearance. Results: Gall bladder volume increased from group I to group III (0.08 ± 0.06 to 1.06 ± 0.93 ml). Bile flow increased significantly from group I to IV (0.13 ± 0.05 to 0.34 ± 0.07 μl/min/g liver weight, p < 0.05). This was associated with significant increases in total bile acid excretion (16 ± 3.6 to 31 ± 2.5 m.Eq/l, p < 0.05). The composition of bile also showed maturational changes with increasing postnatal age. Sodium taurocholate and secretin increased the bile flow significantly in all groups. Conclusion: Data from these studies clearly demonstrate that the bile flow and bile acid excretion is immature in preterm and term baboons when compared to 7- and 60-day-old baboons. The present studies also suggest that baboons can be used as a model to study the postnatal maturation of hepatic excretory function.

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“…Furthermore, cynomolgus monkeys and humans both express FGF19 in the same tissues and are similar with regard to their cholesterol and bile acid synthesis. 63 Cynomolgus monkeys were thus chosen as the most pharmacologically relevant animal model for safety assessment because of comparable high affinity and neutralization activity of BIO-7 for both human and cynomolgus monkey FGF19.…”

Section: Bio-7mentioning

confidence: 99%

Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment

Brennan

Cavagnaro

McKeever

et al. 2017

mAbs

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Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.

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The use of nonhuman primates in the study of bilirubin metabolism and bile secretion

Cited by 8 publications

References 59 publications

Prevention of neonatal hyperbilirubinaemia in non-human primates by Zn-protoporphyrin

Prevention of neonatal hyperbilirubinaemia in non-human primates by Zn-protoporphyrin

Bile Flow and Composition in Preterm, Term and Infant Baboons

Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment

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