Effects of Green Tea Extracts on the Pharmacokinetics of Quetiapine in Rats

Quetiapine is an atypical antipsychotic, used clinically in the treatment of schizophrenia, acute mania in bipolar disorders, and bipolar depression in adults. In this study, the effect of green tea extracts (GTE) on the pharmacokinetics of quetiapine (substrate of CYP3A4) was investigated in rats. Male Wistar albino rats received GTE (175 mg/kg) or saline (control) by oral gavage for 7 days before a single intragastric administration of 25 mg/kg quetiapine. Plasma concentrations of quetiapine were measured up to 12 h after its administration by a validated ultraperformance liquid chromatography-tandem mass spectroscopy. Pretreatment with GTE produced significant reductions in the maximum plasma concentration and area under the curve of quetiapine by 45% and 35%, respectively, compared to quetiapine alone. However, GTE did not produce significant change in elimination half-life and oral clearance of quetiapine. This study concluded that GTE may decrease the bioavailability of quetiapine when coadministered.

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Catechin Bioavailability Is Reduced in Obese Persons Without Altering Gut Microbial-Derived Valerolactones Following Consumption of a Green Tea Extract Confection

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_101 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 468-468

Author(s):

Geoffrey Sasaki ◽

Yael Vodovotz ◽

Zhongtang Yu ◽

Richard Bruno

Keyword(s):

Green Tea ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Relative Bioavailability ◽

Green Tea Extract ◽

Maximum Plasma ◽

Gut Permeability ◽

Epicatechin Gallate ◽

Obesity Status ◽

Tea Extract

Abstract Objectives Green tea extract (GTE) protects against obesity in rodents by reducing gut permeability that otherwise provokes endotoxemia-mediated inflammation. However, whether obesity affects catechin bioavailability and microbial metabolism is unknown. We hypothesized that obesity will reduce catechin bioavailability by increasing microbial biotransformation of catechins. Methods Obese persons (n = 10 M/7F; 33.5 ± 0.7 kg/m2) and age-matched healthy persons (n = 10 M/9F; 21.7 ± 0.4 kg/m2) completed a pharmacokinetics (PK) trial in which a GTE confection [290 mg epigallocatechin gallate (EGCG), 87 mg epigallocatechin (EGC), 39 mg epicatechin (EC), 28 mg epicatechin gallate (ECG)] was ingested prior to collecting plasma at 0, 0.25, 0.5, 1, 2, 3, 5, 8, 10, and 12 h and urine from 0–4, 4–8, 8–12, and 12–24 h. Stool samples were collected and gut permeability was assessed prior to the 12-h PK trial. Plasma and urinary catechin/catechin-derived microbial metabolites were assessed following enzymatic hydrolysis by LC-MS. Results Regardless of health status, relative bioavailability, based on plasma area under the curve (AUC0–12 h), of GTE catechins were: EGCG > EGC > ECG > EC. However, obese persons had 24–27% lower plasma AUC0–12 h for the four catechins compared to lean persons (P < 0.05). They also had 18–36% lower maximum plasma concentrations (Cmax) of GTE catechins but 12 h plasma catechin concentrations were unaffected by obesity status (P > 0.05). 3ʹ,4ʹ-γ-valerolactone (3,4-VL) was detected in the plasma of all participants, while 3ʹ,4ʹ,5ʹ-γ-valerolactone (3,4,5-VL) was detected in 74% and 82% of lean and obese persons, respectively. Plasma AUC0–12 h for these VL metabolites did not differ by obesity status. EGC, EC, 3,4-VL, and 3,4,5-VL, but not EGCG and ECG, were primarily present in urine and urinary total VLs were increased compared with total urinary catechins. However, 24-h urinary excretion of catechins and VLs were unaffected by obesity. Conclusions Obesity reduces GTE catechin bioavailability and Cmax independent of any change in VL metabolite appearance or urinary elimination of catechins, suggesting a gut-level mechanism that limits catechin absorption. Funding Sources Supported by USDA-NIFA and the Foods for Health Discovery Theme at The Ohio State University.

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Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666181122124012 ◽

2019 ◽

Vol 19 (1) ◽

pp. 31-45

Author(s):

Meena K. Yadav ◽

Laxmi Tripathi

Keyword(s):

Anticonvulsant Activity ◽

Computational Study ◽

Plasma Concentrations ◽

Elimination Rate ◽

Area Under The Curve ◽

Preclinical Study ◽

In Vivo Studies ◽

Maximum Plasma ◽

Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

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Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽

10.3390/pharmaceutics13060778 ◽

2021 ◽

Vol 13 (6) ◽

pp. 778

Author(s):

Bettina Gerner ◽

Oliver Scherf-Clavel

Keyword(s):

Hepatic Impairment ◽

Kinase Inhibitor ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Enterohepatic Recirculation ◽

Maximum Plasma ◽

Good Precision ◽

Physiologically Based Pharmacokinetic ◽

Starting Point ◽

Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

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Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00326-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 7

Author(s):

Wendy Ankrom ◽

Ka Lai Yee ◽

Rosa I. Sanchez ◽

Adedayo Adedoyin ◽

Li Fan ◽

...

Keyword(s):

Plasma Concentration ◽

Renal Impairment ◽

Severe Renal Impairment ◽

Geometric Mean ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Transcriptase Inhibitor ◽

Maximum Plasma ◽

Minor Effect ◽

Minimal Impact

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0–∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.)

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Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7077 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7077-7077

Author(s):

Jennifer Ann Woyach ◽

Joseph M. Flynn ◽

Jeffrey Alan Jones ◽

Leslie A. Andritsos ◽

Margaret Lucas ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Dose Range ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Lymphocytic Leukemia ◽

Maximum Plasma ◽

Maximal Dose

7077 Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m2 with remainder given at doses starting at 27 mg/m2 for dose level 1 with escalation to 56 mg/m2. Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ≥ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m2. This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.

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Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain

Anesthesiology ◽

10.1097/aln.0000000000002145 ◽

2018 ◽

Vol 128 (5) ◽

pp. 943-952 ◽

Cited By ~ 8

Author(s):

Dennis M. Fisher ◽

Peter Chang ◽

D. Russell Wada ◽

Albert Dahan ◽

Pamela P. Palmer

Keyword(s):

Plasma Concentration ◽

Acute Pain ◽

Healthy Subjects ◽

Time Course ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Rapid Onset ◽

Maximum Plasma ◽

Mixed Effect ◽

Sublingual Tablet

Abstract Background Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. Methods Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. Results Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. Conclusions The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

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Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial

Antibiotics ◽

10.3390/antibiotics9120931 ◽

2020 ◽

Vol 9 (12) ◽

pp. 931

Author(s):

Philipp Simon ◽

David Petroff ◽

David Busse ◽

Jana Heyne ◽

Felix Girrbach ◽

...

Keyword(s):

Half Life ◽

High Performance ◽

Subcutaneous Tissue ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Volume Of Distribution ◽

Controlled Clinical Trial ◽

Morbidly Obese ◽

Maximum Plasma ◽

The Impact

Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. Methods: Obese (body mass index (BMI) ≥ 35 kg/m2) and age-/sex-matched nonobese (18.5 kg/m2 ≥ BMI ≤ 30 kg/m2) surgical patients received a short-term infusion of 1000-mg meropenem. Concentrations were determined via high performance liquid chromatography-ultraviolet (HPLC-UV) in the plasma and microdialysate from the interstitial fluid (ISF) of subcutaneous tissue up to eight h after dosing. An analysis was performed in the plasma and ISF by noncompartmental methods. Results: The maximum plasma concentrations in 15 obese (BMI 49 ± 11 kg/m2) and 15 nonobese (BMI 24 ± 2 kg/m2) patients were 54.0 vs. 63.9 mg/L (95% CI for difference: −18.3 to −3.5). The volume of distribution was 22.4 vs. 17.6 L, (2.6–9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, −1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05–0.37) and fairly similar area under the curve (AUC)8h (78.7 vs. 89.2 mg*h/L, −21.4 to 8.6). In the ISF, the maximum concentrations differed significantly (12.6 vs. 18.6 L, −16.8 to −0.8) but not the AUC8h (28.5 vs. 42.0 mg*h/L, −33.9 to 5.4). Time above the MIC (T > MIC) in the plasma and ISF did not differ significantly for MICs of 0.25–8 mg/L. Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T > MIC, so dose adjustments for obesity seem unnecessary.

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The Pharmacokinetics of Buserelin after Intramuscular Administration in Pigs and Cows

10.21203/rs.3.rs-900328/v1 ◽

2021 ◽

Author(s):

Zhengrong Gao ◽

Yu Liu ◽

Yuxin Yang ◽

Yuying Cao ◽

Jicheng Qiu ◽

...

Keyword(s):

Area Under The Curve ◽

Apparent Volume ◽

Ultra Performance Liquid Chromatography ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Elimination Half ◽

Liquid Chromatography Tandem Mass ◽

Stability Method ◽

Apparent Volume Of Distribution

Abstract Background: Buserelin is a LHRH agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not clearly understood. This study was designed to develop a sensitive method to determine the concentration of buserelin and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows. Results: A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studies in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h·ng/mL for pigs and 5.63 ±1.86 h·ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ±0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2λz), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals. Conclusion: This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.

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Pharmacokinetic Alteration of Baclofen by Multiple Oral Administration of Herbal Medicines in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/402126 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Tae Hwan Kim ◽

Gi-Young Park ◽

Soyoung Shin ◽

Dong Rak Kwon ◽

Won Sik Seo ◽

...

Keyword(s):

Oral Administration ◽

Plasma Concentrations ◽

Herbal Medicines ◽

Area Under The Curve ◽

Maximum Plasma ◽

Time Profiles ◽

Elimination Half ◽

Repeated Doses ◽

Lower Maximum ◽

Western Drug

The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) andAchyranthes bidentata radix(AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42–4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (Cmax) and longer time to reachCmax(Tmax) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (Furine). The absorption rate (Ka) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

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Effect of intramuscular methadone on pharmacokinetic data and thermal and mechanical nociceptive thresholds in the cat

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x15605164 ◽

2016 ◽

Vol 18 (11) ◽

pp. 875-881 ◽

Cited By ~ 3

Author(s):

Louisa S Slingsby ◽

John W Sear ◽

Polly M Taylor ◽

Joanna C Murrell

Keyword(s):

Antinociceptive Effect ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Blood Collection ◽

Pharmacokinetic Data ◽

Maximum Plasma ◽

Time Data ◽

Mechanical Threshold ◽

Liquid Chromatography Tandem Mass ◽

Methadone Concentration

Objectives The aim of the study was to assess simultaneous pharmacokinetics and thermal and mechanical antinociception after intramuscular methadone (0.6 mg/kg) in 10 cats. Methods Thermal and mechanical threshold (TT and MT, respectively) testing and blood collection were conducted at baseline and up to 24 h after administration. Methadone plasma concentrations were determined by liquid chromatography–tandem mass spectrometry and pharmacokinetic parameters were estimated by a non-compartmental method. TT and MT were analysed using ANOVA ( P <0.05). Time of maximum plasma concentration (Tmax), time of onset of antinociception and time of reaching cut-out threshold (TT 55°C; MT 30 Newtons [N]) were determined. Results TT and MT increased above baseline from 20–240 mins and 5–40 mins, respectively, after intramuscular (IM) administration ( P <0.005). Mean maximum delta T (measured as TT minus baseline threshold) was 7.9°C (95% confidence interval [CI] 4.3–11.6) at 60 mins and mean maximum delta F (measured as MT minus baseline threshold) was 4.2 (95% CI 1.6–6.7) N at 45 mins. IM methadone concentration–time data decreased curvilinearly, and gave a clearance estimate of mean 9.1 ml/kg/min (range 5.2–15.7) with median Tmax at 20 mins (range 5–360 mins). Conclusions and relevance IM data followed classical disposition and elimination in all cats. Plasma concentrations after IM administration were associated with an antinociceptive effect, including negative hysteresis. These data can be used for devising dosing schedules for methadone in clinical feline practice.

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