Man versus Beast: Pharmacokinetic Scaling in Mammals

Mordenti, Joyce

doi:10.1002/jps.2600751104

Cited by 359 publications

(213 citation statements)

References 40 publications

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“…The t 1/2 of DEX in rats is 5.5 h (12), and drug t 1/2 in mice is typically about one-half that in rats (13). Thus, it is likely that DEX was mostly cleared within 24 h in our study.…”

Section: Immunosuppressive Treatments and Experimental Designmentioning

confidence: 80%

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Keil¹,

Luebke

Pruett

2001

The Journal of Immunology

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Although reductionist experimental designs are excellent for identifying cells, molecules, or functions involved in resistance to particular microbes or cancer cells, they do not provide an integrated, quantitative view of immune function. In the present study, mice were treated with either dexamethasone (DEX) or cyclosporin A (CyA), and immune function and host resistance were evaluated. Multivariate statistical methods were used to describe the relative importance of a broad range of immunological parameters for host resistance in mice treated with various dosages of DEX. Multiple regression and logistic regression analysis indicated that changes in 24 immunological parameters explained a substantial portion of the changes in resistance to B16F10 tumor cells or streptococcus group B. However, at least 40% of the change in host resistance remained unexplained. DEX at all dosages substantially suppressed numerous relevant immunological parameters, but significantly decreased resistance to Listeria monocytogenes only at the highest dosage. In contrast, CyA substantially decreased resistance to L. monocytogenes at dosages that caused relatively minor suppression of just a few immunological parameters (unfortunately, CyA data and host resistance data for L. monocytogenes were not suitable for multivariate analysis). These results illustrate that mathematical models can be used to explain changes in host resistance on the basis of changes in immune parameters, and that moderate changes in relevant immunological parameters may not produce the types of changes in host resistance expected on the basis of results from reductionist experimental designs.

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“…The t 1/2 of DEX in rats is 5.5 h (12), and drug t 1/2 in mice is typically about one-half that in rats (13). Thus, it is likely that DEX was mostly cleared within 24 h in our study.…”

Section: Immunosuppressive Treatments and Experimental Designmentioning

confidence: 80%

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Keil¹,

Luebke

Pruett

2001

The Journal of Immunology

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“…To take into account known physiological dependencies between the toxicokinetic model parameters (e.g., between organ volumes and body weight, or alveolar ventilation rate and cardiac output) several of them were linked to the lean body mass or other parameter values via scaling functions (15)(16)(17)(18) (Table 1 fp, for which such truncation would be meaningless, and the body weight. In setting uncertainties (but not for variabilities), we tried to be conservative and set the prior variances higher rather than lower when there was ambiguity in the biological literature (for example, with the metabolic parameters).…”

Section: A Priori Parameter Distibutionsmentioning

confidence: 99%

Population Toxicokinetics of Benzene

Bois¹,

Jackson²,

Pekari³

et al. 1996

Environmental Health Perspectives

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In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of benzene in humans. We derive statistical distributions for the parameters of a physiological model of benzene, on the basis of existing data. The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between benzene exposure (up to 10 ppm) and fraction metabolized in the bone marrow is obtained and is shown to be linear for the subjects studied. Our median population estimate for the fraction of benzene metabolized, independent of exposure levels, is 52% (90% confidence interval, 47-67%). At levels approaching occupational inhalation exposure (continuous 1 ppm exposure), the estimated quantity metabolized in the bone marrow ranges from 2 to 40 mg/day.

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“…The leaves are also used for the treatment of scratches, sores and wounds caused by dogs, cats and mice. Fresh leaves may be pressed on the gum for the treatment of stomatitis, skin cancer and nervousness (8), suppuration, acne, boils, abscesses, tetanus, rabies (58), colic, convulsion (27), cough, sore throat and insomnia (33). Aqueous extract of the plant has haematinic and plasma expander effects in mice (38).…”

Section: Introductionmentioning

confidence: 99%

The Paradox of Human Equivalent Dose Formula: A Canonical Case Study of Abrus Precatorius Aqueous Leaf Extract in Monogastric Animals

Saganuwan¹,

Onyeyili²

2016

Macedonian Veterinary Review

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There is abundant literature on the toxicity of A. precatorius seeds. However there is a need to define the toxicity limit of the Abrus precatorius leaf in monogastric animals. Human Equivalent Dose (HED) which is equal to animal dose multiplied by animal km (metabolism constant) divided by human km was used to project the LD 50 of fifteen monogastric animals , where human km factor is body weight (kg) divided by body surface area (m 2 ). Human Equivalent No-observable Adverse Effect Doses were determined by multiplying the animal no-observable adverse effect dose by animal weight (Wa) divided by human weight (Wh). The LD 50 of the aqueous leaf extract of Abrus precatorius in mice was estimated to be between 2559.5 and 3123.3 mg/kg body weight. The LD 50 extrapolated from mouse to rat (1349.3-1646.6 mg/kg), hamster (1855.3-2264.1 mg/kg), guinea pig (1279.5-1561.4 mg/kg), rabbit (618.4-754.7 mg/kg), monkey (593.7-724.5 mg/kg), cat (392.7-479.2 mg/kg), dog and baboon (371.1-452.8 mg/kg), child (297-362 mg/kg) and adult human (197.8-241.5 mg/kg) body weight respectively could be a reality. The therapeutic safe dose range for the animals was 1-12.5 mg/kg body weight for a period of 7 days, but at a dose (≤ 200 mg/kg body weight) the leaf extract showed haematinic effect. However, at a higher dose (> 200 mg/kg), the extract showed haemolytic activity in rats, whereas at a dose (≥25.0 mg/kg), the leaf extract might be organotoxic in hamster, guinea pig, rabbit, monkey, cat, dog, baboon, child and adult human if administered orally for a period of 7 days.

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Man versus Beast: Pharmacokinetic Scaling in Mammals

Cited by 359 publications

References 40 publications

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Population Toxicokinetics of Benzene

The Paradox of Human Equivalent Dose Formula: A Canonical Case Study of Abrus Precatorius Aqueous Leaf Extract in Monogastric Animals

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