Pharmacokinetic studies in dogs

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

Pharmacokinetic studies in dogs demonstrated a 3.5-fold increase in oral bioavailability of phenytoin when administered as the disodium phosphate prodrug versus sodium phenytoin [54]. A few additional examples of investigations with this strategy include the steroids betamethasone [55] and hydrocortisone [56], HIV protease inhibitors [57], and the anticancer drug etoposide [58,59]. Comprehensive reviews of this strategy are also available [52,60,61]. 

The serine protease tryptase is released from mast cells at sites of inflammation. Thus, tryptase inhibitors have potential for treating inflammatory disorders, such as asthma, allergic rhinitis, and inflammatory bowel disease. We explored a series of spirocyclic piperidine amide derivatives (1) as tryptase inhibitors and identified 2 (JNJ-27390467) as a potent, selective inhibitor of human p-tryptase (Ki = 3.7 nM). This compound has -700-fold selectivity vs. inhibition of trypsin, and greater selectivity vs. inhibition of 12 other serine proteases. In pharmacokinetics studies in dogs and rats, 2 showed... 

Gabizon AA, Barenholz Y, Bialer M. Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing polyethylene glycol-derivatized phospholipid pharmacokinetic studies in rodents and dogs. Pharm Res 1993 10(5) 703. 

Pharmacokinetic studies in mice, rats, and dogs showed that cephapirin was readily metabolized into desacetylcephapirin. The rate and the extent of this metabolism showed a decreasing tendency from rodents to dogs. In these species, the plasma elimination half-lives of cephapirin and desacetylcephapirin were 0.4-0.9 h. In dairy cows, cephapirin was mainly eliminated by the urinary route and, to a smaller extent, by the biliary route. 

Pharmacokinetic studies in horses, cattle, sheep, and dogs have shown that the differences between the four species were remarkably small (112). After intravenous administration of xylazine, systemic half-lives ranged from 22 min... 

HPLC with column switching and mass spectrometry was applied to the online determination and resolution of the enantiomers of donepezil HC1 in plasma [38]. This system employs two avidin columns and fast atom bombardment-mass spectrometry (FAB-MS). A plasma sample was injected directly into an avidin trapping column (10 mm x 4.0 mm i.d.). The plasma protein was washed out from the trapping column immediately while donepezil HC1 was retained. After the column-switching procedure, donepezil HC1 was separated enantioselectivity in an avidin analytical column. The separated donepezil HC1 enantiomers were specifically detected by FAB-MS without interference from metabolites of donepezil HC1 and plasma constituents. The limit of quantification for each enantiomer of donepezil HC1 in plasma was 1.0 ng/ml and the intra-and inter-assay RSDs for the method were less than 5.2%. The assay was validated for enantioselective pharmacokinetic studies in the dog. 

PURPOSE AND RATIONALE Dogs have been extensively used to study renal physiology and the action of diuretics. Renal physiology of the dog is claimed to be closer to man than that of rats. Oral absorbability of diuretic substances can appropriately be studied in dogs. Using catheters, interval collections of urine can be made with more reliability than in rats. Simultaneously, blood samples can be withdrawn to study pharmacokinetics. 

Engelen AJM, Rodrigues de Miranda JF and Ariens EJ, Pharmacokinetics of renal contrast media. I. Renal excretion processes studied in dogs by the stop-flow technique. Invest. Rad., 8, 210-218 (1973). 

Pharmacokinetic studies used to be carried out on a single compound at a time, but in order to improve throughput the concept of cassette or N-in-1 dosing was introduced. In this case, N refers to the number of co-administered compounds, often about five including a standard. Figure 9.41 shows data from a 5-in-l study in dog and clearly points out the... 

In a preclinical study in dogs, there was no pharmacokinetic interaction between hydroxycarbamide and anagrelide, therefore no clinical pharmacokinetic interaction is expected. ... 

S. Wallis, B. Charles, L. Gahan, L. Filippich, M. Bredhauer, and P. Duckworth, Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog, J. Pharm. ScL, 85, 803-809 (1996). 

Children s Susceptibility. No studies were located in which comparisons were made between the sensitivity of children and adults to the toxicity of americium. Animal studies indicate that juvenile dogs are less susceptible than adults to americium-induced bone cancer (Lloyd et al. 1999). No direct evidence was located to indicate that the pharmacokinetics of americium in children may be different from that in adults. Based on dosimetric considerations related to differences in the parameters of available models, as well as studies in animals, it seems likely that children may be more susceptible to americium toxicity than are adults by virtue of age-related differences in pharmacokinetics. Absorption of ingested americium may be as much as 200 times greater in neonatal animals than in adults. (Bomford and Harrison 1986 David and Harrison 1984 Sullivan et al. 1985). 

The main pre-clinical species used for pharmacokinetic studies are the rat, mouse and dog. An examination of the Biosys database for 2000 and 2001 shows that of the abstracted papers, 6334 mapped to the subject heading Pharmacokinetics . Of these, the vast majority (70%) were studies on humans. Studies on rats constituted 14% of the reports, mice 7.5% and dogs 3.4% (Table 6.2). Nonhuman primates can also be important pharmacokinetic models, but ethical and practical considerations severely limit studies in these animals such that, within the same period, they represented less than 0.5% of the abstracted reports on PK. 

The improved solubility properties of these compounds lead to excellent oral absorption properties. Compound (47), which exhibits the best overall properties in this study, attains better blood levels in mouse when administered at 25 mg kg, p.o. than does tosufloxacin at 100 mg kg , p.o. It is interesting to note that the epimer of (47) (compound (48)), which is less active inherently but possesses even better solubility, achieves an outstanding Cmax of 12.4 fig ml Compound (47) also exhibits excellent pharmacokinetic properties after oral administration in dog. 

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