Jejunal permeability and hepatic extraction of fluvastatin in humans

Lindahl, Anders; Sandström, Rikard; Ungell, Anna‐Lena; Abrahamsson, Bertil; Knutson, Tina W.; Knutson, Lars; Lennernäs, Hans

doi:10.1016/s0009-9236(96)90145-9

Cited by 73 publications

(66 citation statements)

References 27 publications

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“…The HLM CL int, u, met values for these compounds are 22, 29, 76, and 128 ml/min per milligram, respectively , smaller than the value for telmisartan [395 ml/min per milligram microsomal protein with bovine serum albumin (Gill et al, 2012), 1212 ml/min per milligram microsomal protein with bovine serum albumin (this study)]. However, their mean half-lives (3.4, 1.78, 1, and 1.2 hours, respectively) are much shorter than that of telmisartan (20 hours) (Lindahl et al, 1996;Weber et al, 1996;Muck et al, 1997;Stangier et al, 2000b;Niemi et al, 2005). To address the inconsistency between in vitro and in vivo observations, we hypothesize that telmisartan glucuronide is converted by intestinal microflora into telmisartan, and telmisartan experiences enterohepatic recirculation.…”

Section: Modeling and Simulations Of Plasma Pk During Elimination Phasescontrasting

confidence: 53%

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Ghosh

Maurer

et al. 2014

Drug Metab Dispos

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A previously developed physiologically based pharmacokinetic model for hepatic transporter substrates was extended to an organic anion transporting polypeptide substrate, telmisartan. Predictions used in vitro data from sandwich culture human hepatocyte and human liver microsome assays. We have developed a novel method to calibrate partition coefficients (Kps) between nonliver tissues and plasma on the basis of published human positron emission tomography (PET) data to decrease the uncertainty in tissue distribution introduced by in silico-predicted Kps. With in vitro data-predicted hepatic clearances, published empirical scaling factors, and PET-calibrated Kps, the model could accurately recapitulate telmisartan pharmacokinetic (PK) behavior before 2.5 hours. Reasonable predictions also depend on having a model structure that can adequately describe the drug disposition pathways. We showed that the elimination phase (2.5-12 hours) of telmisartan PK could be more accurately recapitulated when enterohepatic recirculation of parent compound derived from intestinal deconjugation of glucuronide metabolite was incorporated into the model. This study demonstrated the usefulness of the previously proposed physiologically based modeling approach for purely predictive intravenous PK simulation and identified additional biologic processes that can be important in prediction.

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Section: Modeling and Simulations Of Plasma Pk During Elimination Phasescontrasting

confidence: 53%

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Ghosh

Maurer

et al. 2014

Drug Metab Dispos

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“…3 and the plasma concentration and urinary excretion data after intravenous administration in the clinical studies and f B values (Singhvi et al, 1990; FDA-approved package). In the case of fluvastatin, F H was calculated by dividing its bioavailability (0.33) by the fraction absorbed in humans (0.9) because its hepatic clearance (16 ml/min/kg) was close to the hepatic blood flow rate (Tse et al, 1992;Lindahl et al, 1996). F H of pitavastatin was obtained from the following equation (eq.…”

Section: The Rate-determining Process In Hepatic Eliminationmentioning

confidence: 99%

Investigation of the Rate-Determining Process in the Hepatic Elimination of HMG-CoA Reductase Inhibitors in Rats and Humans

Watanabe

Kusuhara²,

Maeda³

et al. 2009

Drug Metab Dispos

184

144

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ABSTRACT:Elucidation of the rate-determining process in the overall hepatic elimination of drugs is critical for predicting their intrinsic hepatic clearance and the impact of variation of sequestration clearance on their systemic concentration. The present study investigated the rate-determining process in the overall hepatic elimination of the HMG-CoA reductase inhibitors pravastatin, pitavastatin, atorvastatin, and fluvastatin both in rats and humans. The uptake of these statins was saturable in both rat and human hepatocytes. Intrinsic hepatic clearance obtained by in vivo pharmacokinetic analysis in rats was close to the uptake clearance determined by the multiple indicator dilution method but much greater than the intrinsic metabolic clearance extrapolated from an in vitro model using liver microsomes. In vivo uptake clearance of the statins in humans (pravastatin, 1.44; pitavastatin, 30.6; atorvastatin, 12.7; and fluvastatin, 62.9 ml/ min/g liver), which was obtained by multiplying in vitro uptake clearance determined in cryopreserved human hepatocytes by rat scaling factors, was within the range of overall in vivo intrinsic hepatic clearance (pravastatin, 0.84-1.2; pitavastatin, 14-35; atorvastatin, 11-19; and fluvastatin, 123-185 ml/min/g liver), whereas the intrinsic metabolic clearance of atorvastatin and fluvastatin was considerably low compared with their intrinsic hepatic clearance. Their uptake is the rate-determining process in the overall hepatic elimination of the statins in rats, and this activity likely holds true for humans. In vitro-in vivo extrapolation of the uptake clearance using a cryopreserved human hepatocytes model and rat scaling factors will be effective for predicting in vivo intrinsic hepatic clearance involving active uptake.Predicting the pharmacokinetic properties of drug candidates in preclinical stages of development has been a critical issue for avoiding failure in clinical stages of development because of pharmacokinetics. The liver is the major clearance organ for drugs in the body where the inactivation mechanisms are composed of metabolic enzymes and drug transporters. These inactivation mechanisms are associated with the hepatic first-pass effect after oral administration and with elimination from the systemic circulation. It is well accepted that, because of large species differences in drug metabolism, the results of animal studies cannot be directly extrapolated to humans. Instead, in vitro systems have been developed to replace animal studies and provide reliable predictions. In particular, human liver microsomes enable the reliable prediction of the metabolic clearance of drugs in the liver of humans (Iwatsubo et al

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“…Class I drugs should therefore be the best candidates for extended-release product development, which is borne out by virtue of several extended-release formulations being based on class I compounds (Corrigan 1997). Metoprolol is such a drug; it has been shown to be a high permeability drug in the human jejunum, as determined with the Loc-I-Gut technique, and its BA did not differ after administration by intubation in different regions of the intestine ( Figure 5) (Lindahl et al 1996). Consequently, metoprolol has a complete fraction dose absorbed and also high permeability in the colon.…”

Section: The Bcs In the Pharmaceutical Development Phasementioning

confidence: 99%

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

Lennernäs

Abrahamsson

2005

Journal of Pharmacy and Pharmacology

Self Cite

184

119

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Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediaterelease (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.

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Jejunal permeability and hepatic extraction of fluvastatin in humans

Cited by 73 publications

References 27 publications

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

Investigation of the Rate-Determining Process in the Hepatic Elimination of HMG-CoA Reductase Inhibitors in Rats and Humans

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

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