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Metabolism Studies (metabolism + studies)
Kinds of Metabolism Studies Selected AbstractsBimatoprost: A Novel Antiglaucoma AgentCARDIOVASCULAR THERAPEUTICS, Issue 2 2004D. F. Woodward ABSTRACT The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a ,-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2, -ethanolamide (prostamide F2,), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties. [source] Electrochemical, Chemical and Enzymatic Oxidations of PhenothiazinesELECTROANALYSIS, Issue 17 2005B. Blankert Abstract The oxidation of several phenothiazine drugs (phenothiazine, promethazine hydrochloride, promazine hydrochloride, trimeprazine hydrochloride and ethopropazine hydrochloride) has been carried out in aqueous acidic media by electrochemical, chemical and enzymatic methods. The chemical oxidation was performed in acetic acid with hydrogen peroxide or in formate buffers using persulfate. The enzymatic oxidation was performed in acetate or ammonium formate buffer by the enzyme horseradish peroxidase in the presence of H2O2. Molecules with, in the lateral chain, two carbon atoms (2C) separating the ring nitrogen and the terminal nitrogen, showed two parallel oxidation pathways, that is (i) formation of the corresponding sulfoxide and (ii) cleavage of the lateral chain with liberation of phenothiazine (PHZ) oxidized products (PHZ sulfoxide and PHZ quinone imine). Molecules with three carbon atoms (3C) separating the two nitrogens were oxidized to the corresponding sulfoxide. The chemical oxidation of all the studied molecules by hydrogen peroxide resulted in the corresponding sulfoxide with no break of the lateral chain. Oxidation by persulfate yielded, for the 3C derivatives, only the corresponding sulfoxide, but it produced cleavage of the lateral chain for the 2C derivatives. The origin of the distinct oxidation pattern between 2C and 3C molecules might be related to steric effects due to the lateral chain. The data are of interest in drug metabolism studies, especially for the early search. In the case of 2C phenothiazines, the results predict the possibility of an in vivo cleavage of the lateral chain with liberation of phenothiazine oxidized products which are known to produce several adverse side effects. [source] Synthesis of 14C-labeled piperidines and application to synthesis of [14C]SCH 351125, a CCR5 receptor antagonistJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 7 2007Sumei Ren Abstract 1-Benzyl-4-hydroxy[2- 14C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [14C]formaldehyde in high yield. The distribution pattern of 14C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza-Cope rearrangement. These steps precede the rate-determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [14C]SCH 351125, required for metabolism studies, was prepared from 1-benzyl-4-hydroxy[2- 14C]piperidine in six steps. [14C]SCH 351125 is a mixture of four atropisomers. Preparation of [14C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd. [source] M+4 stable isotope labeling of levovirin and M+7 and carbon-14 labeling of levovirin valinate pro-drugJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 14 2006Steve A. de Keczer Abstract [M+4]-labeled levovirin 5 (231 mg) was synthesized as an MS reference compound from [M+4] triazole ester 2. [M+7]-labeled levovirin valinate 6 (127 mg) was synthesized as a comparison MS reference compound from [M+6] triazole ester 3. [14C]-Levovirin 7 and [14C]-levovirin valinate 8 were synthesized to support metabolism studies. The synthesis of 7 was accomplished in 33% overall yield (35.4 mCi, 57 mCi/mmol) from Ba14CO3 and 8 was synthesized in 41% yield (12.5 mCi, 57 mCi/mmol) from 7. An efficient metallation/carbonation reaction was developed to synthesize [14C]-triazole ester 4. Copyright © 2006 John Wiley & Sons, Ltd. [source] Synthesis of [phenyl-U- 14C]aryl and [8- 14C]carboxy labeled tracers of vorinostatJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 5 2006Eric D. Soli Abstract In support of a program to develop a treatment for advanced, refractory cutaneous T-cell lymphoma, two differentially [14C]-labeled forms of vorinostat, a histone deacetylase inhibitor, were synthesized for use in metabolism studies. Copyright © 2006 John Wiley & Sons, Ltd. [source] Syntheses of deuterated jasmonates for mass spectrometry and metabolism studiesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2005Patrycja W. Galka Abstract Jasmonic acid and its metabolites play an essential role in the regulation of plant development and systemic defense responses. Isotopically labeled standards are required to quantify plant hormones for metabolism studies using mass spectrometry. A convenient method for the preparation of deuterated analogs of jasmonates is demonstrated. Modification of commercially available methyl jasmonate by base-catalyzed proton/deuterium exchange or Wittig reaction introduces either two or three heavy atoms into a molecule. Copyright © 2005 John Wiley & Sons, Ltd. [source] The syntheses of [14C] and [13C2,15N3]aprepitantJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2004Charles S. Elmore Abstract In support of a program to develop a treatment for chemotherapy-induced nausea and vomiting, two isotopically labeled forms of neurokinin-1 receptor antagonist aprepitant have been synthesized. A [l4C]-labeled version was synthesized for use in metabolism studies, while a [13C2,15N3]-labeled version was synthesized for use in a study to determine the bioavailability of the final market image. Both syntheses utilized labeled chloroacetonitrile which was synthesized in two steps from labeled potassium cyanide. Copyright © 2004 John Wiley & Sons, Ltd. [source] Synthesis of [14C]-labelled vardenafil hydrochloride and metabolitesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2003D. Seidel Abstract For studies of pharmacokinetics and drug metabolism of the new orally active, selective phosphodiesterase type V (PDE V) inhibitor vardenafil (Levitra®), the 14C-labelled version was synthesised. Starting from the cyanation of 2-iodophenol with K14CN, an 8-step synthesis led to two batches with 0.727 g (2.857 GBq) and 2.199 g (5.497 GBq) of [triazinone- 14C]vardenafil hydrochlo-ride with different specific radioactivities. The label was located in position 2 of the imidazotriazinone moiety. Several carbon-14 labelled metabolites were synthesised as reference compounds for metabolism studies. Copyright © 2003 John Wiley & Sons, Ltd. [source] Measurement of caffeine and five of the major metabolites in urine by high-performance liquid chromatography/tandem mass spectrometryJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 3 2005Allan Weimann Abstract Analysis of caffeine and its metabolites is of interest with respect to caffeine exposure, for kinetic and metabolism studies and for opportunistic in vivo estimation of drug metabolizing enzyme activity in humans and animals. For the latter, analysis is usually done by high-performance liquid chromatography (HPLC) with UV detection. However, this method is close to the detection limit for certain of the metabolites and requires very long chromatography, 30,60 min. We have developed a fast method for the quantification of caffeine and its metabolites 1-methylxanthine, 1-methyluric acid, 1,7-dimethyluric acid, 5-acetylamino-6-amino-3-methyluracil (AAMU) and 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by HPLC tandem mass spectrometry (MS/MS) in urine that requires only its dilution with buffer and centrifugation before injection into the HPLC/MS/MS system. The chromatography lasts 7 min and is followed by 4.5 min for re-equilibration of the HPLC column, giving a total analysis time of 11.5 min. The method provides a great sensitivity improvement with detection limits for all analytes ,25 nM in real samples. Also, the analysis provides much improvement in capacity to ,125 samples per 24 h. Intra- and inter-day coefficients of variation of a single analysis are <6.5% for all the analytes. The inter-day coefficient of variation of duplicate analyses is <4.8% for all analytes. The method is automated, including automated integration, and it is fast, robust and suitable for large-scale investigations in humans and animals. Copyright © 2005 John Wiley & Sons, Ltd. [source] The novel N -substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuseJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008Ahmed A. Othman Abstract GA2-50 is a novel N -substituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2-50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse. In vitro transport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2-50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2-50 showed high transcellular permeability despite being a P-glycoprotein substrate. GA2-50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values. In vivo, GA2-50 showed high brain uptake (Ri,,,10), large volume of distribution (Vss,=,37 L/kg), and long elimination half-life (t˝,=,19 h). GA2-50 resulted in 1.6- and 2.7-fold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2-50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2-50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2-50 possesses several attributes sought after for a substitute medication for cocaine abuse. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source] Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2-methoxyestradiolJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2007Nehal J. Lakhani Abstract The aim of this study was to characterize the metabolic pathways of 2-methoxyestradiol (2ME2), an investigational anticancer drug. In vitro metabolism studies were performed by incubation of 2ME2 with human liver microsomes under various conditions and metabolite identification was performed using liquid chromatography-tandem mass spectrometry. In microsomal mixtures, four major oxidative metabolites and two glucuronic acid conjugates were observed originating from 2ME2. Human liver S9 protein fraction was used to screen for in vitro sulfation but no prominent conjugates were observed. The total hepatic clearance as estimated using the well-stirred model was approximately 712 mL/min. In vivo metabolism, assessed using 24-h collections of urine from cancer patients treated with 2ME2 revealed that <0.01% of the total administered dose of 2ME2 is excreted unchanged in urine and about 1% excreted as glucuronides. Collectively, this suggests that glucuronidation and subsequent urinary excretion are elimination pathways for 2ME2. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1821,1831, 2007 [source] Evaluation of the environmental fate of thymol and phenethyl propionate in the laboratoryPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 7 2008Dingfei Hu Abstract BACKGROUND: The natural monoterpenoid pesticides thymol and phenethyl propionate (PEP) are used indoors and outdoors, but their fate in the environment has not been reported. In order better to understand their impact on the environment, water metabolism and soil metabolism studies were conducted with thymol and PEP at a concentration of 10 µg g,1 in water and in soil under laboratory conditions. RESULTS: Dissipation half-lives of thymol and PEP were 16 and 5 days in water and 5 and 4 days in soil. 2-Phenylethanol and 2-(4-hydroxyphenyl)ethanol were detected as primary degradation products of PEP. Over time, a considerable volatilization loss of thymol, but not of phenethyl propionate, was found in the 1 month study under the experimental conditions used. Less than 6% of thymol and PEP were detected as bound residues, and less than 3% were mineralized during the 30 day study. CONCLUSION: In order to maximize the pesticidal effect, more attention should be paid to the temperature for thymol than for PEP when they are being applied, owing to the high volatility of the former. Thymol and PEP pose low risks to the ecosystem because of their rapid dissipation and low bound residues in the environment. Copyright © 2008 Society of Chemical Industry [source] Toxicological determination and in vitro metabolism of the designer drug methylenedioxypyrovalerone (MPDV) by gas chromatography/mass spectrometry and liquid chromatography/quadrupole time-of-flight mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 18 2010Sabina Strano-Rossi A method for the toxicological screening of the new designer drug methylenedioxypyrovalerone (MDPV) is described; with an emphasis on its application for anti-doping analysis. The metabolism of MDPV was evaluated in vitro using human liver microsomes and S9 cellular fractions for CYP450 phase I and uridine 5,-diphosphoglucuronosyltransferase (UGT) and sulfotransferase (SULT) phase II metabolism studies. The resulting metabolites were subsequently liquid/liquid extracted and analyzed using gas chromatography/mass spectrometry (GC/MS) as trimethylsilyl (TMS) derivatives. The structures of the metabolites were further confirmed by accurate mass measurement using a liquid chromatography/quadrupole time-of-flight (LC/QTOF) mass spectrometer. The studies demonstrated that the main metabolites of MDPV are catechol and methyl catechol pyrovalerone, which are in turn sulfated and glucuronated. The method for the determination of MDPV in urine has been fully validated by assessing the limits of detection and quantification, linearity, repeatability, and accuracy. This validation demonstrates the suitability for screening of this stimulant substance for anti-doping and forensic toxicology purposes. Copyright © 2010 John Wiley & Sons, Ltd. [source] Evaluation of the metabolism of propranolol by linear ion trap technology in mouse, rat, dog, monkey, and human cryopreserved hepatocytesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2009Todd M. Baughman Propranolol is a widely used quality control and validation compound for liver microsome and hepatocyte metabolism studies. A multitude of literature reports describing the identification of propranolol metabolites exists today. However, no literature reports currently exist showing hepatocyte metabolism across the five species commonly used during pre-clinical drug discovery, namely mouse, rat, dog, monkey, and human. Herein, we present full metabolic profiles of propranolol in mouse, rat, dog, monkey and human hepatocytes. As expected, extensive phase I and phase II metabolism was observed across all five species and species-specific metabolites were detected in monkey and dog hepatocytes. Of particular interest was the detection of an N -hydroxylamine glucuronide metabolite in monkey and dog hepatocytes. Copyright © 2009 John Wiley & Sons, Ltd. [source] Extracting metabolite ions out of a matrix background by combined mass defect, neutral loss and isotope filtrationRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 2 2009Filip Cuyckens Mass defect, neutral loss and isotope filtration techniques were applied to electrospray ionization mass spectrometry (ESI-MS) data obtained for in vivo and in vitro samples of drug metabolism studies. A combination of these post-acquisition processing techniques was shown to be more powerful than the use of one of these tools alone for the detection in complex matrices of metabolites of candidate drugs with a characteristic isotope pattern (e.g. containing bromine, chlorine, or a high proportion of radiolabeled drug (12C/14C)) or characteristic neutral losses. In combination with ,all-in-one' data acquisition this methodology is able to perform software-driven constant neutral loss scanning for an unlimited number of mass differences at any time after analysis. Highly selective MS chromatograms were obtained with excellent correlation with their corresponding radiochromatograms. Copyright © 2009 John Wiley & Sons, Ltd. [source] Characterisation of sulphoxides by atmospheric pressure ionisation mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2005Patricia Wright An observation that a series of proprietary compounds containing a methyl thiophenyl group all underwent metabolic S-oxidation, and that the product ion spectra of the resulting S-oxides showed methyl radical loss under low-energy atmospheric pressure ionisation tandem mass spectrometry (API-MS/MS) conditions, has led to an investigation of the fragmentation of commercially available sulphoxides. The phenyl methyl sulphoxides studied do lose methyl radicals under MS/MS conditions on triple quadrupole mass spectrometers. In addition, the phenyl sulphoxides, with simple substituents other than a methyl group, also showed a tendency to lose the substituent as a radical. It was concluded that radical loss from these simple sulphoxides was characteristic of S-oxidation of these molecules. Radical losses, such as those reported here, are used in-house to distinguish S-oxidation from N- and C-oxidation in metabolism studies. Copyright © 2005 John Wiley & Sons, Ltd. [source] Liquid chromatography/tandem mass spectrometric quantification with metabolite screening as a strategy to enhance the early drug discovery processRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 12 2002Philip R. Tiller Throughput for early discovery drug metabolism studies can be increased with the concomitant acquisition of metabolite screening information and quantitative analysis using ultra-fast gradient chromatographic methods. Typical ultra-fast high-performance liquid chromatography (HPLC) parameters used during early discovery pharmacokinetic (PK) studies, for example, employ full-linear gradients over 1,2,min at very high flow rates (1.5,2,mL/min) on very short HPLC columns (2,×,20,mm). These conditions increase sample throughput by reducing analytical run time without sacrificing chromatographic integrity and may be used to analyze samples generated from a variety of in vitro and in vivo studies. This approach allows acquisition of more information about a lead candidate while maintaining rapid analytical turn-around time. Some examples of this approach are discussed in further detail. Copyright © 2002 John Wiley & Sons, Ltd. [source] Assessment of estradiol and its metabolites in meatAPMIS, Issue 1 2001D. MAUME Most studies related to research on steroids in main edible tissues (muscle, liver or kidney) have focused on measurement of parent or major metabolite residues. In order to evaluate the estradiol content in bovine edible tissues, a multi-step extraction procedure was developed in conjunction with parallel metabolism studies of [14C],17,-estradiol in cattle (1,2). Various classes of free estradiol and conjugates were separated: estradiol ,17, and ,17,, estradiol-17-fatty acid esters, estradiol 17-glycoside, estradiol 3,glucuronide, estradiol,17-glycoside and 3- glucuronide (diconjugates) were separated. No sulphates conjugated forms have been found at the detection level of the method. The quantification was realized by calibration with deuterated 17, -estradiol -d3 standard and was validated at the ng kg,1 (ppt) level. Muscle, liver, kidney and fat samples from control or Revalor S® single (licensed implantation) or multi-implanted steers have been assayed. The results show a wide variation between animals, but both the highest value and the mean of total estradiol content in each group proportionally increase from untreated to multi-implanted animals. In accordance with international rules, a calculation of the daily food supply of estradiol by such edible tissues in comparison with the acceptable daily intake was performed. [source] Metabolites in safety testing: metabolite identification strategies in discovery and developmentBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2009Angus N. R. Nedderman Abstract The publication of the FDA MIST guidelines in 2008, together with the acknowledged importance of metabolism data for the progression of novel compounds through drug discovery and drug development, has resulted in a renewed focus on the metabolite identification strategies utilised throughout the pharmaceutical industry. With the plethora of existing and emerging technologies available to the metabolite identification scientist, it is argued that increased diligence should be applied to metabolism studies in the early stages of both drug discovery and drug development, in order to more routinely impact chemical design and to comply with the concepts of the MIST guidance without re-positioning the definitive radiolabelled studies from there typical place in late development. Furthermore, these strategic elements should be augmented by a broad and thorough understanding of the impact of the derived metabolism data, most notably considerations of absolute abundance, structure and pharmacological activity, such that they can be put into proper context as part of a holistic safety strategy. The combination of these approaches should ensure a metabolite identification strategy that successfully applies the principles of the MIST guidance throughout the discovery/development continuum and thereby provides appropriate confidence in support of human safety. Copyright © 2009 John Wiley & Sons, Ltd. [source] Evaluation of SupermixTM as an in vitro model of human liver microsomal drug metabolismBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2002Karthik Venkatakrishnan Abstract SUPERMIXTM is a commercially available formulation of insect cell-expressed human drug-metabolizing cytochrome P450 (CYP) isoforms, mixed in proportions that are optimized to parallel their relative activities in human liver microsomes. We have evaluated the apparent functional affinity and capacity of individual CYP isoforms in SUPERMIXTM in comparison with microsomes from a panel of 12 human livers, using enzyme kinetic studies of isoform-selective index reactions. In addition, we have measured the concentration of NADPH cytochrome P450 oxidoreductase (OR) in SUPERMIXTM and compared it with the concentrations of this accessory electron transfer protein in human liver microsomes. No important differences were evident in the catalytic activities of CYPs 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 between SUPERMIXTM and human liver microsomes. However, SUPERMIXTM lacks CYP2B6 activity and did not hydroxylate the antidepressant bupropion, a clinically relevant substrate of this enzyme. In addition, the concentration of OR in SUPERMIXTM (1198 pmol mg protein,1) is 17-fold higher than the mean value in human liver microsomes (70 pmol mg protein,1). In conclusion, SUPERMIXTM lacks CYP2B6 activity and contains supraphysiological concentrations of the accessory electron transfer protein OR. These factors should be considered when this formulation is used as an in vitro model in human liver microsomal drug metabolism studies. Copyright © 2002 John Wiley & Sons, Ltd. [source] Cell kinetic studies in the murine ventral tongue epithelium: thymidine metabolism studies and circadian rhythm determinationCELL PROLIFERATION, Issue 2002C. S. Potten Abstract. ,The oral mucosa is a rapidly replacing body tissue that has received relatively little attention in terms of defining its cell kinetics and cellular organization. The tissue is sensitive to the effects of cytotoxic agents, the consequence of which can be stem cell death with the subsequent development of ulcers and the symptoms of oral mucositis. There is considerable interest in designing strategies to protect oral stem cells and, hence, reduce the mucositis side-effects in cancer therapy patients. Here we present details of a new histometric approach designed to investigate the changing patterns in cellularity in the ventral tongue mucosa. This initial paper in a series of four papers presents observations on the changing patterns in the labelling index following tritiated thymidine administration, which suggest a delayed uptake of tritiated thymidine from a long-term intracellular thymidine pool, a phenomenon that will complicate cell kinetic interpretations in a variety of experimental situations. We also provide data on the changing pattern of mitotic activity through a 24-h period (circadian rhythms). Using vincristine-induced stathmokinesis, the data indicate that 54% of the basal cells divide each day and that there is a high degree of synchrony in mitotic activity with a mitotic peak occurring around 13.00 h. The mitotic circadian peak occurs 9-12 h after the circadian peak in DNA synthesis. The data presented here and in the subsequent papers could be interpreted to indicate that basal cells of BDF1 mice have an average turnover time of about 26-44 h with some cells cycling once a day and others with a 2- or 3-day cell cycle time. [source] | |||||||||||||