Species differences in pharmacodynamics: Some examples

Appreciation of species variation in response to drugs is essential for the most effective application of available drugs in each species. Such variation may be due to differences in responding systems in different species. These may be: anatomical or histological differences; differences in receptor type and distribution; or differences in the nature and distribution of intermediary substances. This paper discusses examples of species differences in response related to pharmacodynamics, concentrating on 4 groups of substances: namely substances (1) involved in anaphylactic reactions, (2) acting on the sympathetic nervous system, (3) affecting the central nervous system, and (4) with effects on the reproductive system.

1. In anaphylactic reactions the release, distribution and effects of mediators, including histamine, 5-hydroxytryptamine, dopamine, kinins, slow reacting substance of anaphylaxis (SRS-A), eosinophil chemotactic factor, neutrophil chemotactic factor, platelet activating factor and prostaglandins, vary. The distribution of H₁ and H₂-histamine receptors for example varies even between different species of ruminants. Successful inhibition of anaphylactic or allergic reactions necessitates the correct choice of antagonist for the affected species, e.g. antihistamines may be expected to be effective in guinea pigs and dogs but prostaglandin antagonists would be more useful in cattle.
2. Sympathomimetics and α and β adrenergic receptor blocking drugs have different metabolic effects and effects on sweating in different species, e.g. horses, ruminants and rats.
3. Substances, including analgesics and anaesthetics, which affect the central nervous system, may produce depression in some species but excitation in others (e.g. morphine, ketamine) due to differences in distribution of neurotransmitters. Some drug susceptibilities are genetically controlled.
4. The effects of substances on the reproductive systems of different species can be more readily predicted as differences in the regulation of oestrus are appreciated.

Species variation in responses to immunostimulants and antibiotics are also referred to. Theoretically the responses of different species to a given drug might be predicted from a full understanding of the pharmacology of the drug and of comparative physiology, biochemistry and anatomy. In practice this is frequently not possible.     

Species differences in the hepatic biotransformation of zearalenone

Zearalenone (ZEA), a Fusarium toxin, is frequently found in animal feed materials. It is known to exert oestrogenic effects in all animals tested but susceptibility varies between species, possibly reflecting differences in the metabolic processing of ZEA, which predominantly involves hydroxylations, assumed to be catalysed by 3alpha- and 3beta- hydroxysteroid dehydrogenases, as well as conjugation with glucuronic acid. In this study, the biotransformation of ZEA by hepatic subcellular fractions of various domestic animals was investigated and compared to the rat. Notable inter-species differences in terms of the rate of absolute and relative metabolite production in the different subcellular fractions were identified. The highest amount of alpha-zearalenol (alpha-ZOL) was produced by pig hepatic microsomes (V(max)=795.8+/-122.7pmol/mg/min), whereas in chicken microsomes the highest amounts of beta-zearalenol (beta-ZOL) (V(max)=1524+/-29.7pmol/mg/min) could be measured. Except for sheep and cattle, the efficiency of alpha-ZOL production (expressed as the ratio of apparent V(max)/k(m)) was higher in the microsomal fraction compared to the post-mitochondrial fraction. In contrast, the apparent efficiency of beta-ZOL production was high in pigs, cattle, chickens and rats, but very low in sheep. Conjugation of ZEA with glucuronic acid was investigated, and the results indicated significant inter-species differences in the rate of glucuronidation, which was saturable at low concentrations in all species tested, except pigs. The significant differences between the percentages of glucuronidation of ZEA, alpha-ZOL, and beta-ZOL suggest not only differences in the affinity of the individual substrate, but might also indicate the presence of different isoforms of uridine diphosphate glucuronyl transferases (UDPGTs). The results are of clinical relevance, as they contribute to the understanding of the species-specific susceptibility towards exposure to ZEA.     

Serum ferritin, serum iron, and erythrocyte values in foals

Twenty-one healthy Thoroughbred and Quarter Horse foals were studied from birth until 1 year of age. Foals had access to an iron-supplemented creep feed before weaning and were fed an iron-supplemented concentrate as part of their diet after weaning at 4 months of age. Initial blood samples were taken before foals were allowed to nurse. Serum iron concentration, total iron-binding capacity, and PCV decreased during the foal's first 24 hours of life. Serum iron concentration decreased rapidly from 446 +/- 16 micrograms/dl (mean +/- SE) at birth to 105 +/- 11 micrograms/dl at 3 days of age. Serum ferritin concentration increased from a mean of 85 +/- 8 ng/ml at birth to 159 +/- 11 ng/ml at 1 day of age. Thereafter, ferritin concentration decreased gradually to a minimum of 61 +/- 6 ng/ml at 3 weeks of age, and then at 6 months increased to values similar to those from reference adult horses. The ferritin concentration in colostrum at birth was 354 +/- 42 ng/ml, compared with 25 +/- 2 ng/ml in milk 1 day later. The decrease and then increase in serum ferritin concentration occurred concomitantly with opposite changes in serum total iron-binding capacity. The mean PCV decreased gradually to a minimum at 3 months of age. This decrease was associated with an increasing number of microcytes, as determined with a cell-size distribution analyzer.     

Nonsteroidal anti-inflammatory agents: Species differences in pharmacodynamics

The disposition kinetics and systemic availability of nonsteroidal anti-inflammatory (NSAI) agents as well as their antipyretic and anti-nociceptive properties are reviewed in different species. The anti-inflammatory versus bradykinin, serotonin and kaolin oedema activities of aspirin (ASA), phenylbutazone (PBZ) and indomethacin (IDM) explain their large use in veterinary medicine. The low analgesic effect versus NO₃Ag arthritis, radiant heat and tail pressure of indomethacin and oxyphenbutazone contrasts with the widespread activity of phenazone. The comparative inhibitory effect of NSAI agents on the rat fundus contraction due to arachidonic acid is an indication of their relative inhibition of prostaglandin biosynthesis. Among the side-effects of NSAI agents, the long-lasting hyperactivity and hypomotility induced by a parenteral injection of phenylbutazone in the dog is of importance despite the fact that in this species, as in the horse, the average half life is only 6 h due to side-chain hydroxylation (versus 42 h in man for whom conjugation is a major pathway). Initiation of therapy with a loading dose followed by maintenance doses (each half the size of the loading dose) at constant intervals equal to the half-life of the drug has been shown to be suitable for most drugs with long half-life values. According to this a tentative harmless dosage regimen can be calculated for NSAI therapy in different species.     

The effect of various pH values on in vitro peptic digestion of proteins in the presence of Cu2 ions]

Studies were carried out to investigate the effect of different pH values on the peptic digestion of soya protein in the presence and in the absence of Cu2+ ions. The studies were performed in vitro at a pH of 2.2 and 3.2, with 2.96 X 10(-5) mole of Cu2+ ions present in 11 of the reaction mixture. The reaction was carried out in a digestion apparatus permitting dialysis of the cleavage products. Different parameters were used as criteria of digestion, viz. the quantity of N contained in the reaction vessel (residue) and in the resulting dialysis products as determined by Kjehldahl microanalysis and automatic amino acid analysis, the proportions of digestion products found in the different molecular ranges after partition of Sephadex G 75 and the composition of amino acids in the cleavage products. From the distribution of the reaction products on the residue and dialysis products and on the different molecular ranges it was found that additions of Cu2+ ions at pH 2.2 produced a considerable inhibition of digestion. With a rise in pH to 3.2 peptic digestion decreased even without the addition of Cu2+. Supplementation of Cu2+ ions produced only a slight additional effect in the molecular range termed "exclusion limit". In the case of the amino acids tyrosine and phenylalanine it was found that an increase in pH changed the composition of peptides within the different molecular ranges. Additions of Cu2+ had no influence on the amino acid composition.     

Acid-base values of porcine blood]

The main indices of acid-base balance of venous blood (v. auricularis extrema) were determined in 100 clinically disease-free pigs divided into categories with 20 animals each (piglets, pigs from 30 to 40 kg, pigs from 80 to 100 kg, sows, and boars). The Astrup method was employed for the determination of pH, pCO2, total CO2, BE, BB, AB in individuals, groups, and in the set as a whole. The Astrup PHM 71 and BMS 2 apparatuses were used. The results were summed up in a table and in graphs, including the Siggaard-Andersen curve nomogram. Statistical significance was calculated at p greater than 0.05. The average ABB values were determined in the set of 100 pigs; pH 7.306 +/- 0.013, pCO2 53.4 +/- 1.6 mmHg, total CO2 27.6 +/- 0.5, BE --1.0 +/- 0.4, BB 46.2 +/- 0.7, SB 23.5 +/- 0.4, AB 26.0 +/- 0.5 mEl-1.     

Species differences in hepatic biotransformation of the anthelmintic drug flubendazole

Flubendazole (FLBZ) is a broad‐spectrum benzimidazole anthelmintic used in pigs, poultry, and humans. It has been proposed as a candidate for development for use in elimination programmes for lymphatic filariasis and onchocerciasis in humans. Moreover, FLBZ has shown promise in cancer chemotherapy, particularly for neuroblastoma. This work investigated the hepatic carbonyl‐reducing pathway of FLBZ in different species, including humans. Microsomal and cytosolic fractions were obtained from sheep, cattle, pig, hen, rat, and human liver. Both subcellular fractions of each species converted FLBZ into a reduced metabolite (red‐FLBZ). The rate of microsomal red‐FLBZ production was highest in sheep (1.92 ± 0.13 nmol/min.mg) and lowest in pigs (0.04 ± 0.02 nmol/min.mg); cytosolic red‐FLBZ production ranged from 0.02 ± 0.01 (pig) to 1.86 ± 0.61 nmol/min.mg (sheep). Only subcellular fractions from sheep liver oxidized red‐FLBZ to FLBZ in a NADP⁺‐dependent oxidative reaction. Liver microsomes from both pigs and humans transformed FLBZ to red‐FLBZ and a hydrolyzed metabolite. Very significant differences in the pattern of FLBZ metabolism were observed among the tested species and humans. These results reinforce the need for caution in extrapolating data on metabolism, efficacy, and safety of drugs derived from studies performed in different species.     

Strain differences in the erythrocyte and spermatozoan head dimensions of White Leghorn cocks

Differences amongst the length, breadth and area of erythrocyte nuclei, and the length, breadth, shape and area of the heads of spermatozoa were observed in six strains of White Leghorn cocks. Erythrocyte nuclear and spermatozoan head dimensions were negatively correlated. The negative correlations were explained on the basis of cellular oxidation rate.