Dietary-Induced Obesity and Changes in the Biodistribution and Metabolism of Amiodarone in the Rat

Abdussalam, Ali; Al-Agili, Marwa; Nebaihi, Hamdah M. Al; Mayo, Patrick; Gabr, Raniah Q.; Brocks, Dion R.

doi:10.1016/j.xphs.2018.06.032

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…Metabolite data were not available for this probe, and 6‐hours urinary excretion was low and did not show a significant change after LRYGB. Several studies in rodent models of obesity have demonstrated decreased expression and activity of several CYPs including CYP2C . Similarly, the decrease in CL/F/BW of repaglinide in obese patients compared to reference group was observed.…”

Section: Discussionmentioning

confidence: 73%

“…Several studies in rodent models of obesity have demonstrated decreased expression and activity of several CYPs including CYP2C. 28,29 Similarly, the decrease in CL/F/ BW of repaglinide in obese patients compared to reference group was observed. Interestingly, changes in pharmacokinetic parameters (AUC 0-6 , C max , Cl/F/BW and Vd/F/BW) of repaglinide were "reversed" by surgery to be comparable to those in reference group (Table S3).…”

Section: Discussionmentioning

confidence: 91%

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Laparoscopic Roux‐en‐Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates

Puris

Pasanen

Ranta

et al. 2019

Basic Clin Pharma Tox

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There is a lack of information about the changes in drug pharmacokinetics and cytochrome P450 (CYP) metabolism after bariatric surgery. Here, we investigated the effects of laparoscopic Roux‐en‐Y gastric bypass (LRYGB) surgery on pharmacokinetics of nine drugs given simultaneously which may reveal changes in the activities of the main CYPs. Eight obese subjects undergoing LRYGB received an oral cocktail containing nine drugs, substrates of various CYPs: melatonin (CYP1A2), nicotine (CYP2A6), bupropion (CYP2B6), repaglinide (CYP2C8), losartan (CYP2C9), omeprazole (CYP2C19/CYP3A4), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A). The 6‐hours pharmacokinetic profiles in serum and urine of each drug or corresponding metabolite as well as their metabolic ratios were compared before surgery with those at a median 1 year later. LRYGB exerted variable effects on the pharmacokinetics of these drugs. The geometric mean AUC0‐6 (90% confidence interval) of melatonin, bupropion, repaglinide, chlorzoxazone and midazolam after LRYGB was 27 (19%‐41%), 54 (43%‐67%), 44 (29%‐66%), 160 (129%‐197%) and 74 (62%‐90%) of the pre‐surgery values, respectively. The pharmacokinetics of losartan, omeprazole and dextromethorphan did not change in response to surgery. Nicotine was not detected in serum, while geometric mean of AUC0‐6 of its metabolite, cotinine, increased by 1.7 times after surgery. There were 3.6‐ and 1.3‐fold increases in the AUC ratios of 6‐hydroxymelatonin/melatonin and hydroxybupropion/bupropion, respectively. The cocktail revealed multiple pharmacokinetic changes occurring after LRYGB with the greatest effects observed for CYP1A2, CYP2C8 and CYP2E1 substrates. Future studies should be focused on CYP1A2, CYP2A6, CYP2C8 and CYP2B6 to clarify the changes in activities of these enzymes after LRYGB.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 91%

Laparoscopic Roux‐en‐Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates

Puris

Pasanen

Ranta

et al. 2019

Basic Clin Pharma Tox

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“…Two significant relationships were observed (Figure ), BMI vs t ½ (positive) and age vs CL/ F (negative). In rats, decreases in hepatic blood flow occur with higher age and body weight, as are levels and activities of hepatic cytochrome P450 3A isoforms (involved in lidocaine metabolism) . Hepatic and portal blood flow has been shown to decrease with general anaesthesia, particularly in older patients (>55 years), and mean age of our patients was 63.9 years.…”

Section: Discussionmentioning

confidence: 72%

“…In rats, decreases in hepatic blood flow occur with higher age and body weight, as are levels and activities of hepatic cytochrome P450 3A isoforms (involved in lidocaine metabolism). [32][33][34] Hepatic and portal blood flow has been shown to decrease with general The optimal pharmacokinetic (PK) model as one (1c) or two (2c) are indicated for each patient.…”

Section: Discussionmentioning

confidence: 99%

Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations

Primrose

Nebaihi

Brocks

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Rectus sheath blocks are an established option for analgesia following abdominal surgery, but pharmacokinetic data are limited. This study sought to characterise the absorption of lidocaine injectate and the pharmacokinetics of lidocaine after rectus sheath injection. Methods Bilateral rectus sheath single‐injection blocks were given to 10 patients undergoing general or urological surgery. Afterwards, serial lidocaine serum levels and ultrasound measurements of the rectus sheath injectate reservoir were collected. Key findings Injectate within the rectus sheath was visible with ultrasound up to 12 h after injection. However, the rate of drug absorption exceeded that of injectate disappearance. Peak serum concentration occurred within 30 min with average peak concentrations of 1.65 μg/ml. Lidocaine clearance was lower than reported in young healthy subjects. The body mass index positively correlated with lidocaine terminal phase half‐life, and clearance negatively correlated with age. Conclusions The study provides the first data describing lidocaine pharmacokinetics after rectus sheath injection. Peak serum concentrations transiently achieved systemic levels associated with pain relief after a single bolus injection. The data from this study could be used to develop a regime using single shot rectus sheath blockade with a bolus of lidocaine followed by infusion using bilateral rectus sheath catheters.

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“…Brill et al 25 found that in literature few studies indicate trends towards increased CYP2D6-mediated metabolites in obese versus non-obese patients. However, Abdussalam et al 26 showed that in rats given a high-fat diet CYP2D1 (the equivalent in rat to human CYP2D6) is downregulated. Higher levels of α-hydroxymetoprolol after RYGB might be caused by increased CYP2D6 metabolism due to weight loss.…”

Section: Discussionmentioning

confidence: 99%

Effect of Roux-en-Y gastric bypass on the bioavailability of metoprolol from immediate and controlled release tablets: a single oral dose study before and after surgery

et al. 2019

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Objective Roux-en-Y gastric bypass (RYGB) surgery induces major changes in the gastrointestinal tract that may alter the pharmacokinetics of orally administered drugs. Results from pharmacokinetic studies are sparse. This study aimed to investigate the effect of RYGB on the bioavailability of metoprolol from immediate release (IR) and controlled release (CR) tablets in female patient volunteers before and after surgery. Methods An explorative, two-phase, single oral dose pharmacokinetic study of metoprolol in female patients undergoing RYGB was carried out. The dose was administered twice in each patient, 1 month before and 6 months after surgery. After intake of either 100 mg of metoprolol IR or CR tablet serum concentration-time profiles of metoprolol were determined. The endpoint was the ratio of AUC after /AUC before of metoprolol. results Twelve patients were included in the study (metoprolol IR: 7; metoprolol CR: 5). After intake of a metoprolol IR tablet major intraindividual and interindividual differences for area under the serum concentration versus time curve (AUC) of metoprolol before and after surgery were observed (range ratio AUC 0-10 hours after /AUC 0-10 hours before : 0.74-1.98). For metoprolol CR tablets a significant reduction in bioavailability of metoprolol was observed after surgery (range ratio AUC 0-24 hours after /AUC 0-24 hours before : 0.43-0.77). Conclusion RYGB may influence the bioavailability of metoprolol from an IR tablet. The magnitude of changes in bioavailability after RYGB requires close monitoring of patients using metoprolol IR tablets and dose adjustment if deemed necessary. RYGB clearly reduces the bioavailability of metoprolol from a CR tablet. After RYGB clinicians may consider to increase the dose according to clinical response.

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Dietary-Induced Obesity and Changes in the Biodistribution and Metabolism of Amiodarone in the Rat

Cited by 9 publications

References 21 publications

Laparoscopic Roux‐en‐Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates

Laparoscopic Roux‐en‐Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates

Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations

Effect of Roux-en-Y gastric bypass on the bioavailability of metoprolol from immediate and controlled release tablets: a single oral dose study before and after surgery

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