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P Jeffrey

Publications and source records attributed to P Jeffrey.

43 records · Page 3Linked to original sources
PubMedDate not supplied

Alterations in the cardiopulmonary effects and pharmacokinetics of a bisphosphonate drug by a cytochrome P-450 inhibitor in conscious rats.

U-91502, a bisphosphonate for arthritic inflammation treatment, was evaluated for its parental toxicity. The objective was to differentiate between the parent drug and a reactive metabolite(s) as the proximate cause of the toxic effects using two methods. The first method was to block the metabolism of U-91502 with a broad-spectrum cytochrome P-450 inhibitor, 1-aminobenzotriazole (ABT), to increase its toxicity. The second method was to scavenge any electrophilic intermediates of U-91502 with supplemental nucleophiles, L-methionine (LM) and N-acetylcysteine (NaLc) to decrease its toxicity. Two groups of rats each were given an i.v. injection of saline or ABT followed by an i.v. infusion of U-91502 at a constant dose rate. A third group was given two oral doses of LM followed by a co-infusion of U-91502 and NaLc. The breathing rate (BR) and electrocardiogram (ECG) of the rats were monitored. Blood samples were taken at specified time points for plasma drug concentration analyses (PDC) and pharmacokinetics determination. Each rat was infused until its BR was depressed by approximately 30% from the rates prior to injection of saline or ABT, or the second oral dose of LM. Thereafter, half of the rats in each group were sacrificed immediately and the remaining half at 180 min post infusion. All infused rats, except for those of the co-infusion group, and a group of untreated rats were analyzed for hepatic non-protein sulfhydryl for indication of glutathione depletion. The results indicated that ABT pretreatment expedited the elevation of PDC to a critical level that caused BR and then heart rate (HR) depression and ECG alterations. There was no unusual depletion of glutathione. The maximum concentration and the area under the curve were significantly increased while the total clearance was significantly reduced. Consequently, the postinfusion PDC remained high and the BR and HR depressions persisted. LM and NaLc did not alleviate the toxicity or alter the pharmacokinetics of U-91502. It was concluded that the toxic effects of U-91502 were due mainly to the parent drug and not the metabolites.

Acetylcysteine↗
PubMedDate not supplied

Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat, dog and monkey: in vitro/in vivo correlation and the role of aldehyde oxidase.

1. In vitro studies with the selective dopamine D3 receptor antagonist SB-277011 were conducted in liver microsomes and homogenates from rat, dog, cynomolgus monkey and human to correlate the rate of metabolism with the in vivo pharmacokinetics of the compound in rat, dog and cynomolgus monkey. 2. In the presence of NADPH, SB-277011 was relatively stable in the presence of liver microsomes from rat, dog, cynomolgus monkey and human with an intrinsic clearance (CLi) of < 2 ml min(-1) g(-1) liver for all species. In total liver homogenates, SB-277011 was metabolized at a similar rate in rat and dog (CLi < 2 ml min(-1) g(-1) liver) to that in liver microsomes but in cynomolgus monkey and human (CLi = 9.9 and 45 ml min(-1) g(-1) liver, respectively) the intrinsic clearance was approximately 6- and 35-fold higher, respectively, than that in liver microsomes. 3. In the absence of NADPH, SR-277011 was rapidly cleared in liver homogenates from cynomolgus monkey and human (CLi = 7.4 and 27 ml min(-1) g(-1) liver, respectively) demonstrating that a significant pathway of metabolism of this compound was via an NADPH-independent non-microsomal oxidative route. This pathway was sensitive to inhibition with isovanillin suggesting that the enzyme responsible was aldehyde oxidase. 4. The in vivo pharmacokinetics showed that the plasma clearance of SB-277011 was low in rat (20 ml min(-1) kg(-1)), moderate in dog (14 ml min(-1) kg(-1)) and high in cynomolgus monkey (58 ml min(-1)kg(-1)), which is consistent with the in vitro findings and demonstrated a greater capacity for the monkey to metabolize this compound. The oral bioavailability of SB-277011 in rat, dog and cynomolgus monkey was 35, 43 and 2%, respectively. Given the high clearance of this compound in cynomolgus monkey, the low oral bioavailability is probably as a result of high first-pass elimination, specifically by aldehyde oxidase, rather than poor absorption. 5. The high in vitro clearance of SB-277011 in human liver homogenates and the involvement of aldehyde oxidase in the metabolism of SB-277011 indicates that the bioavailability of the compound is likely to be low in human.

Aldehyde Oxidase↗
PubMedDate not supplied

Utility of metabolic stability screening: comparison of in vitro and in vivo clearance.

1. The ability of hepatic microsomal metabolic stability assessments to predict in vivo clearance in rat has been retrospectively evaluated for 1,163 compounds from 48 programmes of chemistry. Using a simple binary classification system, the in vivo clearances of approximately 64% of the compounds were correctly classified. 2. About 24% of compounds were metalbolically stable yet had clearance greater than half of liver blood flow in vivo. This might be expected as microsomes only contain a limited number of fully functioning drug-metabolizing enzymes and cannot be expected to account for extrahepatic or non-metabolic clearance processes. 3. About 13% of compounds had in vivo clearances of less than half liver blood flow despite being classified as metabolically unstable. Despite overcoming metabolic instability, these compounds had other undesirable properties and were generally more highly bound to plasma proteins, had smaller volumes of distribution (and shorter half-lives despite their clearance) and were more inhibitory against the major human cytochrome P450s. 4. Taking plasma protein binding into consideration reduced the proportion of misclassified low-clearance compounds but did not improve the overall success appreciably. Somewhat surprisingly, human microsomes were nearly as effective as rat microsomes at classifying rat in vivo clearance.

Animals↗
PubMedDate not supplied

Pharmacokinetics and fate of [3H]trospectomycin sulfate, a novel aminocyclitol antibiotic, in male and female dogs and rabbits. Allometric scaling with human.

The pharmacokinetics and fate of [3H]trospectomycin sulfate, a novel aminocyclitol antibiotic, were examined in male and female dogs and rabbits. Total radioactivity levels in plasma were associated with unchanged trospectomycin in both dog and rabbit. No unchanged drug was found in rabbit urine. Two radioactive components were found in dog urine; one was indistinguishable from trospectomycin and the other was probably a degradation product. The disappearance of drug from plasma followed a biphasic pattern and was well described by a bi-exponential function with half-lives of 0.4-0.8 and 30-70 hr in the dog and 0.4 and 90-120 hr in the rabbit. There was a large distribution volume (Vss), which indicated some retention of drug by tissues. The clearance (CL) for both animals was within the normal range for glomerular filtration rate. CL and Vss were not different between the sexes in the dog or rabbit. Excretion in both animals was initially rapid (greater than 40% by 4 hr) and mainly by the urinary route (fecal excretion less than 10%). Urinary excretion was not significantly different between the sexes. Over the dose range of 25-100 mg/kg, the plasma pharmacokinetics in the dog were linear. However, the recovery of radioactivity in the urine was significantly reduced at the highest dose. Trospectomycin CL in rat, human (obtained from previous studies), dog, and rabbit was described by the allometric equation, CL (ml/hr) = 132 x M0.91 where M is the body mass in kg.

Animals↗