Pharmacokinetics of Morphine and Its Surrogates III: Morphine and Morphine 3-Monoglucuronide Pharmacokinetics in The Dog as a Function of Dose

Garrett, Edward R.; Jackson, André J.

doi:10.1002/jps.2600680627

Cited by 59 publications

(28 citation statements)

References 15 publications

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“…Nevertheless, hepatic-derived M3G and exogenously administered M6G are substrates for human and rodent MRP2/Mrp2 and MRP3/Mrp3, which are responsible for their hepatobiliary disposition (Zelcer et al, 2005;van de Wetering et al, 2007;Hasegawa et al, 2010). Biliary excretion, representing up to 20% of morphine glucuronide clearance (Garrett and Jackson, 1979;Ouellet and Pollack, 1995), is mediated by Mrp2. Previous studies examined the pharmacokinetics of M3G in rats with streptozotocininduced diabetes and bile duct ligation-induced cholestasis (Hasegawa et al, 2009(Hasegawa et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Dzierlenga

Clarke

Hargraves

et al. 2014

J Pharmacol Exp Ther

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Morphine is metabolized in humans to morphine-3-glucuronide (M3G) and the pharmacologically active morphine-6-glucuronide (M6G). The hepatobiliary disposition of both metabolites relies upon multidrug resistance-associated proteins Mrp3 and Mrp2, located on the sinusoidal and canalicular membrane, respectively. Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease, alters xenobiotic metabolizing enzyme and transporter function. The purpose of this study was to determine whether NASH contributes to the large interindividual variability and postoperative adverse events associated with morphine therapy. Male Sprague-Dawley rats were fed a control diet or a methionine-and choline-deficient diet to induce NASH. Radiolabeled morphine (2.5 mg/kg, 30 mCi/kg) was administered intravenously, and plasma and bile (0-150 or 0-240 minutes), liver and kidney, and cumulative urine were analyzed for morphine and M3G. The antinociceptive response to M6G (5 mg/kg) was assessed (0-12 hours) after direct intraperitoneal administration since rats do not produce M6G. NASH caused a net decrease in morphine concentrations in the bile and plasma and a net increase in the M3G/morphine plasma area under the concentration-time curve ratio, consistent with upregulation of UDP-glucuronosyltransferase Ugt2b1. Despite increased systemic exposure to M3G, NASH resulted in decreased biliary excretion and hepatic accumulation of M3G. This shift toward systemic retention is consistent with the mislocalization of canalicular Mrp2 and increased expression of sinusoidal Mrp3 in NASH and may correlate to increased antinociception by M6G. Increased metabolism and altered transporter regulation in NASH provide a mechanistic basis for interindividual variability in morphine disposition that may lead to opioid-related toxicity.

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Section: Introductionmentioning

confidence: 99%

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Dzierlenga

Clarke

Hargraves

et al. 2014

J Pharmacol Exp Ther

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“…The glucuronide, the principal metabolite in bile, was only absorbed if first deconjugated by microflora; since, if the intestine was purged of microflora by antibiotics, no absorption took place. When investigated in dog (12) or man (13) similar hydrolyses of glucuronides of other parent compounds by gut microflora have been implicated in enterohepatic cir'culation.…”

Section: Discussionmentioning

confidence: 99%

Enterohepatic circulation in rat and dog of14C-0-[3-(4-<2-methoxyphenyl>-1 -piperazinyl)-2-hydroxypropyl]-3-methoxy-benzaldoxim dihydrochloride and it’s demethylated metabolite

Paul¹,

Illing²,

House³

1981

European Journal of Drug Metabolism and Pharmacokinetics

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14C-0-[3-(4- less than 2-methoxyphenyl greater than -1-piperazinyl)-2-hydroxypropyl]-3-methoxybenzaldoxim dihydrochloride (HWA 923) was well absorbed (approximately 80%) in rat and dog. In normal animals 37-48% of the radioactivity from a 2 mg/kg of body weight oral or parenteral dose was excreted in the urine, and 48-50% in the faeces. When 14C-HWA 923 was given orally to rats with biliary cannulae, only approximately 10% of the dose was excreted in the urine and approximately 68% appeared in the bile. If bile, collected from animals given 14C-HWA 923, was re-infused intraduodenally into surgically prepared rats, approximately 12% was re-excreted in the urine, and approximately 55% re-excreted in the bile. There were considerably higher levels of radioactivity present in rat blood following intravenous administration of 14C-HWA 923 than after an oral dose, suggesting that radioactivity given via the oral route might be excreted directly into the bile without reaching the systemic circulation. In dog, a significant "first-pass" effect was seen for HWA 923. In a surgically prepared dog, where the bile collection was intermittent, 32% of the dose was excreted in the urine and 46% in the bile. An estimated 73% of the dose would have been present in bile, if continuous collection had taken place. In rat, the major urinary metabolite (up to 40% of the urinary radioactivity) was identified, after specific hydrolysis with beta-glucuronidase, as a demethylated product of HWA 923 by co-chromatography in four solvent systems. This metabolite was present, in rat bile as the conjugates (approximately 40% of the biliary radioactivity), together with significant quantities (approximately 20%) of conjugated HWA 923. The two products were also found on hydrolysis o bile, using gut microflora. Similar results were obtained from dog samples. It is postulated that hydrolysis of the glucuronides of unchanged HWA 923 and its demethylated metabolite by gut micro-flora results in enterohepatic circulation of these two compounds in rat and dog.

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“…It is a relatively recent finding that penicillins render 1-3 metabol ites in urine [5], Reassessment of pharmacokinetic prop erties of antimicrobial agents is therefore generally to be recommended. Biotransfor mation may be associated with dose-depen dent pharmacokinetics, as has been well es tablished for acetyl salicylic acid [28], mor phine [22], and a number of other drugs.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of a New Cephalosporin, Cefotaxime (HR 756) in Patients with Different Renal Functions

Bergan¹,

Larsen

Brodwall

1982

Chemotherapy

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The pharmacokinetics of intramuscular doses of 1.0 g cefotaxime (HR 759) was studied in 19 persons with normal or reduced renal function. Quantitation was done by both microbiological and high pressure liquid chromatography (HPLC) methods. The HPLC determined unchanged cefotaxime and desacetyl cefotaxime and up to 2 more metabolites in serum, whether unchanged or biotransformed. Patients with renal functions within the normal range (inulin clearance above 100 ml/min) had a mean serum peak concentration of 24.5 ± 10.5 μg/ml. In renal failure, both serum concentrations and the terminal serum half-life (t½β) increased. The mean terminal serum half-life was 2.1 h according to the microbiological assay and 1.5 h according to the HPLC procedure at a glomerular filtration rate (GFR) of 100 ml/min. At an inulin clearance of 10 ml/min, the serum half-life was 6.0 h for the total microbiologically assayed activity and 3.6 h for unchanged drug. There is a linear relationship between log serum half-life of the three moieties of unchanged cefotaxime, total antimicrobial activity (agar diffusion assay with Escherichia coli as indicator), and the major metabolite desacetyl cefotaxime and log clearance of both inulin (Cl_I) and p-amino-hippuric acid (CI_PAH) down to CI_I^, of 10 ml/min. The excretion of unchanged drug in urine during 24 h was reduced gradually upon reduction in renal function from a mean of 59.4 ± 10.2% (range 52.1–77.1) in 5 subjects with GFR above 100 ml/min. The area volume of distribution, e.g. the area of the one-compartment linear open model or during the β-phase of the two-compartment model, V_d,area, was 34.3 ± 10.4 litres according to the microbiological assay and 27.3 ± 13.4 litres for unchanged cefotaxime in patients with renal function within the normal range. The patients with reduced renal function had only insignificantly different distribution volumes. The volumes in normal individuals correspond to 53% of the body weight. The deasacetyl cefotaxime metabolite is excreted more slowly than the parent compound and elimination is relatively longer compared to the parent compound in patients with reduced renal functions. Doses for patients with reduced renal function are discussed. Because nonrenal mechanisms of elimination assume importance when the renal route becomes inefficient, elimination is only moderately prolonged, even in patients with severe renal impairment. Therefore, only moderate reduction in dosage seems necessary.

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Pharmacokinetics of Morphine and Its Surrogates III: Morphine and Morphine 3-Monoglucuronide Pharmacokinetics in The Dog as a Function of Dose

Cited by 59 publications

References 15 publications

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Enterohepatic circulation in rat and dog of14C-0-[3-(4-<2-methoxyphenyl>-1 -piperazinyl)-2-hydroxypropyl]-3-methoxy-benzaldoxim dihydrochloride and it’s demethylated metabolite

Pharmacokinetics of a New Cephalosporin, Cefotaxime (HR 756) in Patients with Different Renal Functions

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