Prediction of human pharmacokinetics - renal metabolic and excretion clearance.

Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Abstract Text:

Urban Fagerholm,Urban Fagerholm,

The kidneys have the capability to both excrete and metabolise drugs. An understanding of mechanisms that determine these processes is required for the prediction of pharmacokinetics, exposures, doses and interactions of candidate drugs. This is particularly important for compounds predicted to have low or negligible non-renal clearance (CL). Clinically significant interactions in drug transport occur mostly in the kidneys. The main objective was to evaluate methods for prediction of excretion and metabolic renal CL (CL(R)) in humans. CL(R) is difficult to predict because of the involvement of bi-directional passive and active tubular transport, differences in uptake capacity, pH and residence time on luminal and blood sides of tubular cells, and limited knowledge about regional tubular residence time, permeability (P(e)) and metabolic capacity. Allometry provides poor predictions of excretion CL(R) because of species differences in unbound fraction, urine pH and active transport. The correlation between fraction excreted unchanged in urine (f(e)) in humans and animals is also poor, except for compounds with high passive P(e) (extensive/complete tubular reabsorption; zero/negligible f(e)) and/or high non-renal CL. Physiologically based in-vitro/in-vivo methods could potentially be useful for predicting CL(R). Filtration could easily be predicted. Prediction of tubular secretion CL requires an in-vitro transport model and establishment of an in-vitro/in-vivo relationship, and does not appear to have been attempted. The relationship between passive P(e) and tubular fraction reabsorbed (f(reabs)) for compounds with and without apparent secretion has recently been established and useful equations and limits for prediction were developed. The suggestion that reabsorption has a lipophilicity cut-off does not seem to hold. Instead, compounds with passive P(e) that is less than or equal to that of atenolol are expected to have negligible passive f(reabs). Compounds with passive P(e) that is equal to or higher than that of carbamazepine are expected to have complete f(reabs). For compounds with intermediate P(e) the relationship is irregular and f(reabs) is difficult to predict. Tubular cells are comparably impermeable (for passive diffusion), and show regional differences in enzymatic and transporter activities. This limits the usefulness of microsome data and makes microsome-based predictions of metabolic CL(R) questionable. Renal concentrations and activities of CYP450s are comparably low, suggesting that CYP450 substrates have negligible metabolic CL(R). The metabolic CL(R) of high-P(e) UDP-glucuronyltransferase substrates could contribute to the total CL.

Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Publishing Authors By Initials

U Fagerholm,U Fagerholm,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Journal Published:

PUBLICATION TYPE: Review

Journal: The Journal of pharmacy and pharmacology

VOLUME: 59

Page Numbers: 1463-71

Journal Abbreviation: J. Pharm. Pharmacol.

ISSN: 0022-3573

DAY: 2

MONTH: Nov

YEAR: 2007

Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 376363

Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Prediction of human pharmacokinetics - renal metabolic and excretion clearance. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Prediction of human pharmacokinetics - renal metabolic and excretion clearance.

AFFILIATION: Clinical Pharmacology, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden. urban.fagerholdm@astrazeneca.com

Country: England

AGENCY:

GRANT:

ACRONYM:

MEDLINETA: J Pharm Pharmacol

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Prediction of human pharmacokinetics - renal metabolic and excretion clearance Related Publications

• Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding.
• Expression of the focal adhesion protein PINCH in normal and alkali-injured corneas and the role of PMNs.
• Influence of topical treatment on epithelial wound healing and pain in the early postoperative period following photorefractive keratectomy.
• Intestinal bladder augmentation at school age has no adverse effects on growth.
• Messenger RNA levels for genes involved in extracellular matrix from human corneal scrapings before and after photorefractive keratectomy.
• Molecular identification of two strains of third-stage larvae of Contracaecum rudolphii sensu lato (Nematoda: Anisakidae) from fish in Poland.
• Plano and refractive keratectomy. Comparison of the wound healing response.
• Prediction of human pharmacokinetics - renal metabolic and excretion clearance.
• Prediction of human pharmacokinetics--evaluation of methods for prediction of volume of distribution.
• Prediction of human pharmacokinetics--gut-wall metabolism.
• Prediction of human pharmacokinetics--improving microsome-based predictions of hepatic metabolic clearance.
• Prediction of human pharmacokinetics-biliary and intestinal clearance and enterohepatic circulation.
• Proliferating cell nuclear antigen colocalization with corneal epithelial stem cells and involvement in physiological cell turnover.
• Repeated UVR exposures cause keratocyte resistance to apoptosis and hyaluronan accumulation in the rabbit cornea.
• Stroma remodelling during healing of corneal surface irregularities induced by PTK.
• The Role of Permeability in Drug ADME/PK, Interactions and Toxicity-Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans.
• The expression pattern of the subunit of chaperonin containing T-complex polypeptide 1 and its substrate, alpha-smooth muscle actin, during corneal wound healing.
• The highly permeable blood-brain barrier: an evaluation of current opinions about brain uptake capacity.
• The outcome of reoperation following photorefractive keratectomy.
• Wound healing response in the presence of stromal irregularities after excimer laser treatment.