Stereoselective pharmacokinetics and metabolism of flobufen in guinea pigs

Stereoselective aspects of pharmacokinetics and metabolism of a chiral nonsteroidal antiinflammatory drug, flobufen, 4-(2', 4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, were studied in male guinea pigs after p.o. administration of racemic flobufen (rac-flobufen) at a dose of 10 mg/kg. Blood samples were collected at intervals over 16 h after the administration of rac-flobufen for the quantification of flobufen enantiomers and their respective metabolites in plasma by chiral high-performance liquid chromatography (HPLC). Compartmental pharmacokinetic analysis was used to determine pharmacokinetic parameters of R- and S-flobufen. The plasma concentrations of the S- and R-enantiomers differed significantly during the experimental period. The S/R-enantiomeric ratio in 7plasma reached a maximum value of 10.1 at 240 min postdose. The oral clearance value of R-flobufen was five times higher than S-flobufen. The other pharmacokinetic parameters (K(e), T(1/2), V(SS)/F, MRT) of the enantiomers also differed substantially. All four stereoisomers of the dihydrometabolite of flobufen were detected in plasma with varying concentrations. Metabolite 17203 [4-(2,4-difluorophenyl)-phenylacetic acid] exhibited a relatively longer residence time compared to that noted for the enantiomers of the parent compound. Pharmacokinetics of the flobufen enantiomers were stereoselective in guinea pigs. The metabolism of flobufen was complex. However, metabolite 17203 seemed to be the main metabolite of flobufen that may be responsible for its relatively long-lasting antiphlogistic and immunomodulatory effects.     

In vivo pharmacokinetics and in vitro production of cocaethylene in pregnant guinea pigs

Simultaneous exposure to cocaine and ethanol results in the formation of cocaethylene, an active metabolite of cocaine. The concurrent abuse of both cocaine and ethanol is common during human pregnancy, but the kinetics of elimination and formation of this ethyl ester of cocaine have not been studied during pregnancy in any species. In the late gestation guinea pig (61 to 63 days), cocaethylene, at doses of 2 to 4 mg · kg⁻¹, is rapidly eliminated with a half-life of 29 min and a total body clearance of 77 ml · min⁻¹ · kg⁻¹. It is formed enzymatically by hepatic microsomal preparations from fetal, neonatal and maternal guinea pigs. The maximum rate of cocaethylene production (apparent V_max) when either ethanol or cocaine are varied while the other substrate is held constant, increases with age, from the late fetal period (65 days gestation, term 70 days) to adulthood. However, the Michaelis-Menten constant (apparent K_M) does not change with age. The rapid elimination of cocaethylene, coupled with the slow rate of formation (apparent V_max of 140 pmol · min⁻¹ · mg microsomal protein⁻¹) and the small amount of plasma analyzed most likely explains the inability to detect cocaethylene in vivo after concomitant cocaine and ethanol administration.     

Pre- and postnatal toxicity induced in guinea pigs by N-nitrosomethylurea.

Oral administration of N-nitrosomethylurea at maximally tolerated doses to guinea pigs on alternate days from days 34-58 of pregnancy induced prenatal toxicity, as evidenced by a high frequency of stillbirths and intrauterine growth retardation, and postnatal toxicity, as evidenced by stunting and progressive mortality. Similar administration of N-nitrosomethylurethane at maximally tolerated doses did not induce such toxic effects.     

+]-Huperzine A protects against soman toxicity in guinea pigs

The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood–brain barrier (BBB) to protect against central nervous system damage. [−]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [−]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+]-Huperzine A, a synthetic stereoisomer of [−]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+]-Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2× LD₅₀ soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning.     

Effects of zixoryn on pharmacokinetics of antipyrine in intact and sensitized guinea pigs]

The effect of zixoryn, a hepatic inductor of cytochrome P-450, on the pharmacokinetics of antipyrine in intact and sensibilized guinea-pigs was studied. It was found that sensibilization of albumin increased the half-time (T1/2), AUC and decreased the total body clearance (Clt) of antipyrine and the renal clearance (Clr) of metabolites in urine. The administration of zixoryn in sensibilized animals decreased T1/2 and AUC and increased the clearance of antipyrine and its metabolites.     

The association of viral activation with penicillin toxicity in guinea pigs and hamsters

Penicillin toxicity in the guinea pig may be manifested in several different ways, and it is proposed that these toxic effects be categorized into three syndromes: (1) toxic syndrome, characterized by acute fatal illness; (2) hemorrhagic syndrome, characterized by delayed illness with leukopenia and thrombocytopenia, and culminating in massive visceral hemorrhages; (3) chronic syndrome, characterized by retardation of growth and alopecia, a condition somewhat resembling “runt disease.” A virus having some of the properties of a parvovirus has been isolated repeatedly from animals ill or dying of penicillin-induced disease. This finding has been construed as being activation of a latent virus by this antibiotic, but the relationship, if any, of the phenomenon of viral activation to the syndromes produced by penicillin and its frequent lethal toxicity is unknown. That a strong association exists, however, has been established. Of some 60 guinea pigs which received injections of penicillin three developed tumors and four others were found to have gallstones. A virus similar or identical to the guinea pig virus also has been isolated from hamsters dying of penicillin-induced disease. It is hypothesized that the absorption of endotoxin, resulting from the well known change in intestinal flora caused by penicillin, produces a state of immunodeficiency which regularly gives rise to activation of a latent virus, and perhaps, rarely, to the development of malignant neoplasms.     

In silico evaluation of pharmacokinetics and acute toxicity of withanolides in Ashawagandha

Ashwagandha is a medicinal plant used in traditional Asian medicines as an adaptogen to promote both physical and mental health. Withanolides are the major bioactive phytochemicals in Ashwagandha; they are a group of naturally occurring C₂₈-steroidal lactones with an ergostane-based skeleton. Despite the broad use of Ashwagandha, data on the pharmacokinetic and toxicological properties of withanolides remain scarce. Here, 75 withanolides in Ashwagandha were identified in journal publications, databases, and monographs. In silico quantitative structure-activity relationship (QSAR) models were used to evaluate the physicochemical and pharmacokinetic properties as well as the acute toxicity of withanolides. Withanolides had high molecular weight and pKa, low aqueous solubility, and high lipophilicity. QSAR models also predicted high effective human jejunal permeability and plasma protein binding, tissue partitioning, extensive metabolism, hepatic uptake, and renal excretion for certain withanolides. In addition, two thirds of the withanolides evaluated had predicted median lethal dose (LD₅₀) under 100 mg/kg after oral administration in rats. These in silico results could be used to guide further testing and confirmed by in vitro and in vivo studies.     

Comparative evaluation of aloe vera in the management of burn wounds in guinea pigs

An experimental study was designed using Hartley guinea pigs, who received full-thickness burns covering 3 percent of their body surface area by direct contact with a hot plate. A total of 40 animals were equally divided among four modalities of closed burn wound management as follows: group I: silver sulfadiazine (Silvadine); group II: aloe vera gel extract (Carrington Dermal Wound Gel); group III: salicylic acid cream (aspirin); and group IV: plain gauze occlusive dressing only. The dressings were changed daily, and the size and appearance of each burn wound were recorded until complete healing. On the sixth postburn day, quantitative burn wound cultures were made. The average time to complete healing in the control group was 50 days, and the only significant difference was found in the aloe vera-treated animals, which healed on an average of 30 days (p less than 0.02). Wound bacterial counts were effectively decreased by silver sulfadiazine (p = 0.015) and by aloe vera extract (p = 0.015). From our data it appears that aloe gel extracts permit a faster healing of burn wounds.