The Disposition of Theophylline in Blood in Chronic Obstructive Lung Disease

Ebden, P; Banks, James R.; Peel, Tamlyn; Dc, Buss; Pa, Routledge; Bp, Spragg

doi:10.1097/00007691-198612000-00008

Cited by 3 publications

(1 citation statement)

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“…This could be due to the decrease in the protein expression of hepatic CYP1A subfamily, 2B1/2 and 3A subfamily (Table ) than the controls (the in vitro CL int for the disappearance of theophylline not available) because the f p s were comparable between the two groups of rats. The blood/plasma concentration ratio of theophylline in patients with chronic obstructive lung disease was 0.85 ± 0.13 . Note that theophylline pharmacokinetics were dose‐independent in rats after its i.v.…”

Section: Drugsmentioning

confidence: 99%

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Lee

2014

Biopharm & Drug Disp

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Rats with liver cirrhosis induced by N-dimethylnitrosamine (LC) and rats with LC with diabetes mellitus induced by streptozotocin (LCD) have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. Changes in the pharmacokinetics of drugs (mainly non-renal clearance, CL NR ) in LC and LCD rats reported in the literature compared with respective control rats were reviewed. This review mainly explains the changes in the CL NR s of drugs (which are mainly metabolized via hepatic microsomal cytochrome P450s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CL int ; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (f p ) and hepatic blood flow rate (Q H ) depending on the hepatic excretion ratio of the drug. Generally, changes in the CL NR s of drugs in LC and LCD rats could be well explained by the above-mentioned three factors. The mechanism of urinary excretion of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of the drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans.

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Section: Drugsmentioning

confidence: 99%

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Lee

2014

Biopharm & Drug Disp

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Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Chan

Moore³

et al. 2013

Drug Metab Dispos

131

114

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Generating accurate in vitro intrinsic clearance data is an important aspect of predicting in vivo human clearance. Primary hepatocytes in suspension are routinely used to predict in vivo clearance; however, incubation times have typically been limited to 4-6 hours, which is not long enough to accurately evaluate the metabolic stability of slowly metabolized compounds. HepatoPac is a micropatterened hepatocyte-fibroblast coculture system that can be used for continuous incubations of up to 7 days. This study evaluated the ability of human HepatoPac to predict the in vivo clearance (CL) of 17 commercially available compounds with low to intermediate clearance (<12 ml/min per kg). In vitro half-life for disappearance of each compound was converted to hepatic clearance using the well stirred model, with and without correction for plasma protein binding. Hepatic CL, using three individual donors, was accurately predicted for 10 of 17 compounds (59%; predicted clearance within 2-fold of observed human in vivo clearance values). The accuracy of prediction increased to 76% (13 of 17 compounds) with an acceptance criterion defined as within 3-fold. When considering only low clearance compounds (<5 ml/ min per kg), which represented 10 of the 17 compounds, the accuracy of prediction was 60% within 2-fold and 90% within 3-fold. In addition, the turnover of three slowly metabolized compounds (alprazolam, meloxicam, and tolbutamide) in HepatoPac was directly compared with turnover in suspended hepatocytes. The turnover of alprazolam and tolbutamide was approximately 2-fold greater using HepatoPac compared with suspended hepatocytes, which was roughly in line with the extrapolated values (correcting for the longer incubation time and lower cell number with HepatoPac). HepatoPac, but not suspended hepatocytes, demonstrated significant turnover of meloxicam. These results demonstrate the utility of HepatoPac for prediction of in vivo hepatic clearance, particularly with low clearance compounds.

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Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Chan¹,

Moore

et al. 2018

Drug Metab Dispos

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Generating accurate in vitro intrinsic clearance data is an important aspect of predicting in vivo human clearance. Primary hepatocytes in suspension are routinely used to predict in vivo clearance; however, incubation times have typically been limited to 4-6 hours, which is not long enough to accurately evaluate the metabolic stability of slowly metabolized compounds. HepatoPac is a micropatterened hepatocytefibroblast coculture system that can be used for continuous incubations of up to 7 days. This study evaluated the ability of human HepatoPac to predict the in vivo clearance (CL) of 17 commercially available compounds with low to intermediate clearance (<12 ml/min/kg). In vitro half-life for disappearance of each compound was converted to hepatic clearance using the well stirred model, with and without correction for plasma protein binding. Hepatic CL, using three individual donors, was accurately predicted for 11 of 17 compounds (59%; predicted clearance within 2-fold of observed human in vivo clearance values). The accuracy of prediction increased to 82% (14 of 17 compounds) with an acceptance criterion defined as within 3-fold. When considering only low clearance compounds (<5 ml/min per kg), which represented 10 of the 17 compounds, the accuracy of prediction was 70% within 2-fold and 100% within 3-fold. In addition, the turnover of three slowly metabolized compounds (alprazolam, meloxicam, and tolbutamide) in HepatoPac was directly compared with turnover in suspended hepatocytes. The turnover of alprazolam and tolbutamide was approximately 2-fold greater using HepatoPac compared with suspended hepatocytes, which was roughly in line with the extrapolated values (correcting for the longer incubation time and lower cell number with HepatoPac). HepatoPac, but not suspended hepatocytes, demonstrated significant turnover of meloxicam. These results demonstrate the utility of HepatoPac for prediction of in vivo hepatic clearance, particularly with low clearance compounds.

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The Disposition of Theophylline in Blood in Chronic Obstructive Lung Disease

Cited by 3 publications

References 0 publications

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac

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