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S G Jezequel

Publications and source records attributed to S G Jezequel.

9 recordsLinked to original sources
PubMed2003

The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro.

Adult↗
PubMed1999

Role of sialylation in determining the pharmacokinetics of neutrophil inhibitory factor (NIF) in the Fischer 344 rat.

1. Recombinant neutrophil inhibitory factor (NIF) is a glycoprotein. Its amino acid sequence remains constant and has a molecular weight of 28.9 kD. However, approximately 40% of the total molecular weight consists of glycans with variable structure. 2. The pharmacokinetics of 11 different NIF batches with varying extents and patterns of sialylation have been investigated in the Fischer 344 rat following intravenous administration. These data indicate that reducing the extent of NIF sialylation reduces the half-life of the molecule due to an increase in the systemic clearance. Also, an increase in the number of unsialylated or neutral glycans may increase the volume of distribution of NIF, although this effect is marginal. 3. Isolated perfused rat liver (IPRL) investigations have shown that sialylated NIF has a low hepatic extraction (< 1%), while asialo NIF has an extraction that is > 20-fold higher. Co-administration of asialo NIF with asialo fetuin (a protein cleared by hepatic asialoglycoprotein receptor (possibly galactose)-mediated uptake reduced the hepatic extraction of asialo NIF. 4. These data suggest that NIF molecules that have free sugar moieties (possibly galactose) interact with an asialoglycoprotein receptor (possibly galactose-mediated) in the liver (parenchymal cells/hepatocytes). Interaction with this receptor leads to cellular internalization and degradation.

Animals↗
PubMed1996

Modipafant, a new PAF antagonist: pharmacokinetics and disposition in rat, dog and man.

1. The pharmacokinetics and disposition of modipafant, a dihydropyridine PAF antagonist, were studied in rat and dog following intravenous and oral administration of the drug or its radiolabelled analogue. In addition, the pharmacokinetics were studied in man following single administration of escalating oral doses of the drug. Modipafant is a lipophilic weak base with log D(octanol) 7.4 and pKa of 4.3 and 5.3 respectively. 2. Following intravenous administration of [14C]-modipafant to rat, radioactivity is rapidly distributed throughout the body, except for the brain. A significant amount of radioactivity (probably modipafant) is rapidly distributed to the alimentary tract, particularly in the stomach. This is believed to be due to 'ion trapping' of modipafant in the acidic environment of the upper GI tract. The re-circulated modipafant may be subject to reabsorption and/or faecal excretion. 3. Following intravenous administration to rats, systemic clearance is five times greater in the male than female. The magnitude of this difference is in keeping with the clearance of other dihydropyridines such as nilvadipine. In dog, the clearance values are similar for both sexes, as expected. In this latter species, the systemic clearance decreases 6-fold with increasing dose size, indicative of saturation of a pathway of metabolism. 4. Following oral administration over a dose range of 1-12 mg/kg, modipafant is incompletely (27-67%) bioavailable in rat and dog. In the male dog, systemic exposure to drug (AUC/infinity) increased non-linearly with dose. Following oral administration to man, absorption was rapid with a mean value for Tmax of 1 h, and Cmax's ranging non-linearly from 90 to 2100 ng/ml following dosing at 12.5 to 150 mg respectively. 5. The elimination of modipafant is characterized by short half-life (mean values for t1/2 range from 1 to 3 h). However, the nature of the receptor kinetics of modipafant (slow offset) means that the drug shows a long duration of action in spite of short pharmacokinetics at pharmacologically relevant doses. 6. Following oral and intravenous administration of 14C-modipafant to rat and dog, the majority of radioactivity (mean 92%) is recovered in the faeces. The excretion of modipafant in rat and dog is characterized by metabolism, mostly to pyridine metabolites, accounting for between 38 and 75% of total clearance, the rest being cleared as unchanged drug.

Administration, Oral↗
PubMed1994

Fluconazole: interspecies scaling and allometric relationships of pharmacokinetic properties.

Fluconazole is a novel azole antifungal agent with low lipophilicity and high metabolic stability which has been investigated pharmacokinetically in six animal species and in man. The pharmacokinetic parameters of this drug have been compared across species and allometric relationships for fluconazole have been established. The volume of distribution was an 'invariant' parameter. When expressed in units corrected for bodyweight, the volume of distribution was constant across species, in keeping with being distributed throughout body water. Allometric relationships were obtained for total and renal clearance parameters. The closeness of the allometric exponents was in keeping with renal elimination accounting for most of the clearance in all species investigated. It also follows from the invariant characteristics of the volume of distribution term that an allometric relationship for plasma elimination half-life (t1/2) was also evident. Fluconazole thus possesses pharmacokinetic properties which are predictable for all terrestrial mammals. More detailed analysis of renal clearance (CLR) with regard to its relationship with glomerular filtration rate (GFR) has also been carried out. The data suggest that CLR is a direct function of GFR, involves only passive diffusion phenomena and that the extent of tubular re-absorption (approx. 80%) is constant across species. These observations are in keeping with the moderate lipophilicity and plasma protein binding of fluconazole and the incomplete re-absorption of the drug from the kidney tubules. It follows from these investigations that a knowledge of GFR in patients with altered renal function should allow a mechanistically based prediction of elimination characteristics of fluconazole.

Animals↗
PubMed1993

Metabolism of xenobiotics by Beauveria bassiana.

1. Diazepam, warfarin and testosterone were metabolized by whole resting cells of the fungus Beauveria bassiana IMI 12939 via oxidative reactions such as hydroxylation and N-demethylation. 2. Metabolism of each substrate was inhibited by the cytochrome P450 inhibitors SKF-525A and metyrapone, consistent with the involvement of this enzyme system in the metabolism of these drugs by B. bassiana. 3. Substrate concentration-dependent inhibition was observed during diazepam metabolism by this organism, as has been observed in some mammalian systems. 4. Unlike most mammalian P450 systems, the warfarin-metabolizing activity of B. bassiana could not be induced by growing the organism in the presence of phenobarbitone, beta-naphthoflavone, 3-methylcholanthrene, 1-benzylimidazole or warfarin. 5. Overall findings indicate that B. bassiana possesses an oxidative metabolizing system capable of producing metabolites found in mammalian systems.

Chromatography, High Pressure Liquid↗
PubMed1991

The screening of selected microorganisms for use as models of mammalian drug metabolism.

Fifty fungi and two Streptomyces species were screened for their ability to metabolise the probe substrates aminopyrine, diazepam, testosterone, theophylline and warfarin. The metabolism of the 14C-labelled substrates by whole growing cells was compared with that by rat liver microsomes using TLC-autoradiography. Testosterone, warfarin and diazepam were readily metabolised by most microorganisms, and aminopyrine and theophylline were only metabolised by a few. A relationship between substrate lipophilicity and number of microorganisms able to biotransform the substrate was observed, lipophilic substrates being favoured for metabolism, analagous to mammalian cytochrome P-450. A wide variety of metabolites were produced by the screened cultures, with a significant number co-chromatographing with mammalian metabolites. Most microorganisms appeared to exhibit cytochrome P-450-type oxidative reactions such as hydroxylation and N-demethylation, similar to mammalian hepatic microsomal cytochrome P-450 systems.

Animals↗
PubMedDate not supplied

Bioanalytical data in decision making: discovery and development.

1. Bioanalysis is traditionally associated with the development phase of drugs; its use in discovery programmes is often ignored but can have a major impact. 2. Pharmacokinetic studies conducted in conjunction with pharmacology screening can provide additional information to that considered in conventional structure activity relationships. Such factors as half-life and bioavailability can be critical in designing improved drugs. 3. Analytical methods in discovery programmes may differ from those used in later development work: for instance bioassay allows a common assay system for a large number of project compounds. Moreover its use, when combined with conventional methods, such as h.p.l.c., allows active metabolites to be readily detected. 4. Bioanalytical data generated in discovery and pre-clinical programmes are a valuable guide to early clinical programmes. Plasma concentration-response data from these programmes can be compared with those obtained in man. Such comparisons are particularly valuable during the phase one-initial dose escalation study. To maximize this it is our practice to generate pharmacokinetic data between each dose increase.

Animals↗
PubMedDate not supplied

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.

Administration, Oral↗