Estimation of Glomerular Filtration Rate in Cynomolgus Monkeys            (&lt;i&gt;Macaca fascicularis&lt;/i&gt;)

Iwama, Ryosuke; Sato, Tatsusuke; Sakurai, Katsunobu; Takasuna, Kiyoshi; Ichijo, Toshihiro; Furuhama, Kazuhisa; Satoh, Hiroshi

doi:10.1292/jvms.14-0218

Cited by 13 publications

(11 citation statements)

References 11 publications

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“…It is also important to add that the shape of the CL vs. protein size relationship discovered by us should be taken as an approximation of the true relationship, and this relationship should become more robust as we generate more data (especially in the extreme molecular weight ranges) in multiple animal species going forward. Nonetheless, it was found that the intercept of the CL vs. molecular weight relationship for each animal species (0.27 ml/min for mouse, 1.52 ml/min for rat, 4.53 ml/min for rabbit, 15.5 ml/min for monkey, and 96 ml/min for human) was very close to the reported GFR values for each animal species (0.28 ml/min for mouse (15), 1.6 ml/min for rat (17), 5.1 ml/min for rabbit (18), 19 ml/min for monkey (19), and 126 ml/min for human (17)). This suggests that the clearance values predicted by the CL vs. molecular weight relationship are realistic and physiologically relevant for all the animal species evaluated.…”

Section: Discussionsupporting

confidence: 84%

Influence of Molecular size on the clearance of antibody fragments

Krippendorff

Shah

2017

Pharm Res

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Purpose To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice. Methods Two different orthogonal approaches have been used to establish the relationship. First approach uses CL values estimated by non-compartmental analysis (NCA) to establish a correlation with protein size. The second approach simultaneously characterizes the PK data for all the proteins using a 2-compartment model to establish a relationship between protein size and pharmacokinetic (PK) parameters. Results Simple mathematical functions (e.g. sigmoidal, power law) were able to characterize the CL vs. protein size relationship generated using the investigated proteins. The relationship established in mouse was used to predict rat, rabbit, monkey, and human relationships using allometric scaling. The predicted relationships were found to capture the available spares data from each species reasonably well. Conclusions The CL vs. protein size relationship is important for establishing a robust quantitative structure-PK relationship (QSPKR) for protein therapeutics. The relationship presented here can help in a priori predicting plasma exposure of therapeutic proteins, and together with our previously established relationship between plasma and tissue concentrations of proteins, it can predict the tissue exposure of non-binding proteins simply based on molecular weight/radius and dose.

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Section: Discussionsupporting

confidence: 84%

Influence of Molecular size on the clearance of antibody fragments

Krippendorff

Shah

2017

Pharm Res

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“…The Vd ss was estimated to be 181 mL/kg, indicating the extravascular distribution of MGS0008. Similar to the observation in rats, 96.4% of the administered dose was excreted as the unchanged form in urine within 48 hours, and the CL renal was calculated to be 124 mL/h/kg, which was approximately equal to the CL total and GFR in monkeys (184 ± 30 mL/h/kg) 16. Unlike the observations in rats, an oral dose of MGS0008 in monkeys resulted in sustained plasma concentrations at low levels during the observation period up to 24 hours, and the oral bioavailability of MGS0008 was calculated to be only 3.8%.…”

supporting

confidence: 68%

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

Kinoshita

Ochi

Iwata

et al. 2019

Pharmacology Res & Perspec

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MGS0274 besylate is an ester‐based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate could be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half‐life of 16.7 hours; MGS0274 was barely detectable. The oral bioavailability as MGS0008 was 83.7%, which was approximately 20‐fold greater than that after oral dosing of MGS0008 (3.8%). In rats, MGS0008 penetrated the cerebrospinal fluid and was eliminated slower than from plasma. The in vitro metabolism study indicated that MGS0274 was rapidly hydrolyzed to MGS0008, which was not further metabolized. After the intravenous administration of MGS0008 to rats and monkeys, almost all the dose was excreted unchanged in urine. These results suggested that MGS0274 was, as expected, presystemically hydrolyzed to MGS0008 after gastrointestinal absorption and that MGS0008 was distributed throughout the body without further metabolism and ultimately excreted in urine in the animals. Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans.

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“…Blood (0.5 ml) was withdrawn before and 60, 90 and 120 min after the tracer injection. The dose of inulin (50 mg kg −1 ) or iodixanol (40 mg I kg −1 ) and sampling points were selected based on the previous monkey study (Iwama et al ., ). In this study, healthy means non‐treated monkeys at preadministration.…”

Section: Methodsmentioning

confidence: 97%

“…Here, we recently reported that serum clearance of the isotonic, nonionic, dimeric, radiographic contrast medium iodixanol using a multisample strategy without urine collection was a ready‐to‐use tool for screening the GFR in cynomolgus monkeys (Iwama et al ., ). Iodixanol is physiologically inert, stable in plasma, and freely filtered at the glomerulus without secretion or reabsorption in the renal tubules (Svaland et al ., ; Heglund et al ., ; Jacobsen et al ., ).…”

Section: Introductionmentioning

confidence: 97%

A method for estimating the glomerular filtration rate in conscious monkeys

Satoh

Nomiya

Imai

et al. 2015

J of Applied Toxicology

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To establish a method for estimating the glomerular filtration rate (GFR) in conscious monkeys, the radiographic contrast medium iodixanol and the standard agent inulin were coadministered as tracers to male cynomolgus monkeys (Macaca fascicularis) as a bolus injection; blood was collected after 60, 90 and 120 min. An equation based on a single-blood-sample method derived from Jacobsson's formula was prepared using the data from healthy and saline- and gentamicin-treated monkeys by a multisample strategy with iodixanol. The GFR using the equation with iodixanol was in agreement with that from the multisample method with inulin or iodixanol. When the GFR decreased to more than 60% of the basal reference level, serum creatinine concentrations tended to increase, whereas serum blood urea nitrogen concentrations fluctuated. The results suggest that the single-sample-blood method with iodixanol is a practical tool for estimating the monkey GFR in a toxicological research setting therefore minimizing animal sufferings.

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Estimation of Glomerular Filtration Rate in Cynomolgus Monkeys (<i>Macaca fascicularis</i>)

Cited by 13 publications

References 11 publications

Influence of Molecular size on the clearance of antibody fragments

Influence of Molecular size on the clearance of antibody fragments

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia

A method for estimating the glomerular filtration rate in conscious monkeys

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