Metabolic flux analysis of branched-chain amino and keto acids (BCAA, BCKA) and ß-hydroxy ß-methylbutyric acid across multiple organs in the pig.

Branched-chain amino acids (BCAA) and their metabolites the branched-chain keto acids (BCKA) and ß-hydroxy ß-methylbutyric acid (HMB) are involved in the regulation of key signaling pathways in the anabolic response to a meal. However, their (inter)organ kinetics remain unclear. Therefore, branched-chain amino acids (BCAA) [leucine (Leu), valine (Val), isoleucine (Ile)], BCKA [α-ketoisocaproic acid (KIC), 3-methyl-2-oxovaleric acid (KMV), 2-oxoisovalerate (KIV)], and HMB across organ net fluxes were measured. In multi-catheterized pigs (n = 12, ±25 kg), net fluxes across liver, portal drained viscera (PDV), kidney, and hindquarter (HQ, muscle compartment) were measured before and 4 h after bolus feeding of a complete meal (30% daily intake) in conscious state. Arterial and venous plasma were collected and concentrations were measured by LC- or GC-MS/MS. Data are expressed as mean [95% CI] and significance (P < 0.05) from zero by the Wilcoxon Signed Rank Test. In the postabsorptive state (in nmol/kg body wt/min), the kidney takes up HMB (3.2[1.3,5.0]) . BCKA is taken up by PDV (144[13,216]) but no release by other organs. In the postprandial state, the total net fluxes over 4 h (in µmol/kg body wt/4 h) showed a release of all BCKA by HQ (46.2[34.2,58.2]), KIC by the PDV (12.3[7.0,17.6]), and KIV by the kidney (10.0[2.3,178]). HMB was released by the liver (0.76[0.49,1.0]). All BCKA were taken up by the liver (200[133,268]). Substantial differences are present in (inter)organ metabolism and transport among the BCAA and its metabolites BCKA and HMB. The presented data in a translation animal model are relevant for the future development of optimized clinical nutrition.NEW & NOTEWORTHY Branched-chain amino acids (BCAA) and their metabolites the branched-chain keto acids (BCKA) and ß-hydroxy ß-methylbutyric acid (HMB) are involved in the regulation of key signaling pathways in the anabolic response to a meal. Substantial differences are present in (inter)organ metabolism and transport among the BCAA and its metabolites BCKA and HMB. The presented data in a translation animal model are relevant for the future development of optimized clinical nutrition.

Is ß-hydroxy ß-methylbutyrate an effective anabolic agent to improve outcome in older diseased populations?

PURPOSE OF REVIEW: ß-Hydroxy ß-methylbutyrate (HMB) has been used for many years in athletes for muscle buildup and strength, and endurance enhancement. In recent years, its interest quickly expanded in older (diseased) populations and during (exercise) rehabilitation and recovery from hospitalization and surgery. We will discuss recent literature about HMB metabolism, its pharmacokinetics compared with the frequently used metabolite leucine, effectiveness of HMB to improve outcome in older diseased adults, and novel approaches for HMB use. RECENT FINDINGS: HMB supplementation resulted in positive outcomes on muscle mass and functionality, related to its anabolic and anticatabolic properties and prolonged half-life time in blood. Furthermore, it was able to increase the benefits of (exercise) rehabilitation programs to enhance recovery from illness or medical procedures. There is promising evidence that HMB might support bone density, improve cognitive function, and reduce abdominal obesity, which is of importance particularly in the older (diseased) population. SUMMARY: The older diseased population might benefit from dietary HMB because of its established positive properties as well as its long lasting (pharmacological) effect. In addition to evaluating its efficacy and application in various clinical conditions, more research is needed into the mechanisms of action, the optimal dosage, and its potential additional beneficial effects on outcome.

Impact of the calcium form of ß-hydroxy-ß-methylbutyrate upon human skeletal muscle protein metabolism.

BACKGROUND & AIMS: ß-hydroxy-ß-methylbutyrate (HMB) is purported as a key nutritional supplement for the preservation of muscle mass in health, disease and as an ergogenic aid in exercise. Of the two available forms of HMB (calcium (Ca-HMB) salt or free acid (FA-HMB)) - differences in plasma bioavailability have been reported. We previously reported that ∼3 g oral FA-HMB increased muscle protein synthesis (MPS) and reduced muscle protein breakdown (MPB). The objective of the present study was to quantify muscle protein metabolism responses to oral Ca-HMB. METHODS: Eight healthy young males received a primed constant infusion of 1,2 13C2 leucine and 2H5 phenylalanine to assess MPS (by tracer incorporation in myofibrils) and MPB (via arterio-venous (A-V) dilution) at baseline and following provision of ∼3 g of Ca-HMB; muscle anabolic (MPS) and catabolic (MPB) signalling was assessed via immunoblotting. RESULTS: Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 µM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < 0001) and suppressions in MPB (PA: 7.6 ± 1.2 µmol Phe per leg min-1, Ca-HMB: 5.2 ± 0.8 µmol Phe per leg min-1, p < 0.01). Increases in the phosphorylation of mTORc1 substrates i.e. p70S6K1 and RPS6 were also observed, with no changes detected in the MPB targets measured. CONCLUSIONS: These findings support the pro-anabolic properties of HMB via mTORc1, and show that despite proposed differences in bioavailability, Ca-HMB provides a comparable stimulation to MPS and suppression of MPB, to FA-HMB, further supporting its use as a pharmaconutrient in the modulation of muscle mass.

Comparison of availability and plasma clearance rates of ß-hydroxy-ß-methylbutyrate delivery in the free acid and calcium salt forms.

ß-Hydroxy-ß-methylbutyrate (HMB), a leucine metabolite, has long been supplemented as a Ca salt (Ca-HMB) to increase strength and performance gains with exercise and to reduce recovery time. Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB. We also compared the pharmacokinetics of each form when administered mixed in water. Ten human subjects (five male and five female) were studied in a randomised crossover design. There was no significant sex by treatment interaction for any of the pharmacokinetic parameters measured. HMB-FA administered in capsules was more efficient than Ca-HMB capsule at HMB delivery with a 37 % increase in plasma clearance rate (74·8 (sem 4·0) v. 54·5 (sem 3·2) ml/min, P<0·0001) and a 76 % increase in peak plasma HMB concentration (270·2 (sem 17·8) v. 153·9 (sem 17·9) µmol/l, P<0·006), which was reached in one-third the time (P<0·009). When HMB-FA and Ca-HMB were administered in water, the differences still favoured HMB-FA, albeit to a lesser degree. Plasma HMB with HMB-FA administered in water was greater during the early phase of absorption (up to 45 min postadministration, P<0·05); this resulted in increased AUC during the first 60 min after administration, when compared with Ca-HMB mixed in water (P<0·03). In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form.

The relative bioavailability of the calcium salt of ß-hydroxy-ß-methylbutyrate is greater than that of the free fatty acid form in rats.

BACKGROUND: ß-Hydroxy-ß-methylbutyrate (HMB) supplementation has been demonstrated to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. The beneficial effects of HMB have been studied by using either the calcium salt, monohydrate, of HMB (CaHMB) or the free acid form (FAHMB). OBJECTIVE: The present study was designed to compare the pharmacokinetics and relative bioavailability of the 2 forms of HMB administered as a liquid suspension in male Sprague-Dawley rats. METHODS: CaHMB at 30, 100, and 300 mg/kg and equivalent doses of FAHMB at 24.2, 80.8, and 242 mg/kg were administered orally as a liquid suspension to male Sprague-Dawley rats. A single i.v. dose of 5 mg/kg CaHMB, corresponding to an equivalent dose of 4.04 mg/kg FAHMB, was also administered. Plasma concentrations of HMB were analyzed by liquid chromatography tandem mass spectrometry, and pharmacokinetic variables and relative bioavailability of the 2 forms of HMB were determined. RESULTS: After oral administration, the area under the plasma concentration time curve (AUC) from time 0 to time t (0-t) and from time 0 to infinity (0-∞) and the maximum (peak) plasma concentration (Cmax) for CaHMB were significantly greater than for FAHMB, whereas the time to reach Cmax did not differ from that of FAHMB. The relative bioavailability of CaHMB was 49%, 54%, and 27% greater than that of FAHMB for the 3 respective oral doses tested. After i.v. administration, the AUCs 0-t and 0-∞ of the calcium salt were significantly greater than those of FAHMB. The relative bioavailability of CaHMB was 80% greater than that of FAHMB. The higher relative bioavailability of CaHMB may be attributable to its low systemic clearance compared with FAHMB. CONCLUSIONS: This study demonstrates the enhanced relative bioavailability of CaHMB compared with FAHMB. Further studies are warranted to understand the physiologic mechanisms contributing to the differences in systemic clearance.

[ß-hydroxy-ß-methylbutyrate as a dietary supplement (I): metabolism and toxicity]. / El ß-hidroxi-ß-metilbutirato (HMB) como suplemento nutricional (I): metabolismo y toxicidad.

INTRODUCTION: -hydroxy--methylbutyrate (HMB) is a leucine metabolite produced from -ketoisocaproic acid. HMB supplementation has been used as a dietary supplement in sports since 1997, with the aim of decreasing muscle proteolysis. In recent years, positive effects have been reported in different pathologies, which suggests potential health benefits. AIMS: The objectives of this review are: to know both HMB metabolism and toxicity, and to identify HMB cellular and molecular mechanisms of action when used as a dietary supplement. METHODS: A search was performed in the Web of Science, Pubmed and SportDiscus data bases. RESULTS were divided into two parts; this article presents the results about both HMB metabolism and possible toxicity. RESULTS: Studies show that HMB is related to cholesterol metabolism in skeletal muscle, which could reduce proteolysis, through hydroxy-methyl-glutaryl-coenzyme A and mevalonate as a precursor in the synthesis of cholesterol. However, HMB could also be transformed from acetoacetate to beta-hydroxybutyrate by beta-hydrozybutyrate dehydrogenase. The calcium salt of HMB is the most used chemical form in dietary supplements, being the most common dose 3 g of HMB/day. Studies in humans and animals provide evidence that there are no adverse effects associated with HMB supplementation. CONCLUSION: Metabolic effects and lack of toxicity of HMB make it an adequate compound to be used as a dietary supplement.

Introducción: El -hidroxi--metilbutirato (HMB) es un metabolito de la leucina producido a partir del ácido -cetoisocaproico. El HMB se utiliza como suplemento nutricional en el deporte desde 1997, atribuyéndosele una disminución de la proteólisis muscular. En los últimos años, se han descrito efectos positivos del HMB en diversas patologías, lo cual aumenta su probable utilidad para la mejora de la salud. Objetivos: Los objetivos de la presente revisión son: conocer el metabolismo del HMB, así como su absorción y excreción; estudiar la posible toxicidad del HMB; e identificar los mecanismos celulares y moleculares de acción del HMB cuando se utiliza como suplemento nutricional. Métodos: Se utilizaron las bases de datos Web of Science, Pubmed y SportDiscus para realizar la búsqueda de artículos. Los resultados se dividieron en dos partes; en este artículo se abordan el metabolismo y la posible toxicidad del HMB. Resultados: Diversos estudios relacionan al HMB con el metabolismo del colesterol en el músculo esquelético, probablemente reduciendo la proteólisis, a través del 3-hidroxi-3-metilglutaril-coenzima A, que se transforma a mevalonato, actuando como precursor en la síntesis de colesterol. Sin embargo, el HMB podría transformarse en beta-hidroxi-butirato a través del metabolismo del acetoacetato, por medio de la beta-hidroxibutirato dehidrogenasa. Por otra parte, la forma química más habitual en los suplementos nutricionales es la sal de calcio de HMB y la dosis más utilizada, de 3 g de HMB/día. Los estudios realizados en humanos y en animales muestran que no existen efectos adversos por el consumo de HMB. Conclusiones: Los efectos metabólicos y la ausencia de toxicidad del HMB lo hacen adecuado para su uso como suplemento nutricional.

[ß-hydroxy-ß-methylbutyrate as a dietary supplement (II): cell and molecular mechanism of action]. / El ß-hidroxi-ß-metilbutirato (HMB) como suplemento nutricional (II): mecanismos de acción moleculares y celulares.

INTRODUCTION: In recent years, several investigations have related -hydroxy--methylbutyrate (HMB) to a reduced muscle proteolysis and to an increase in muscle mass. Therefore, a number of studies focused on the cellular and molecular mechanisms regulating these effects have been carried out. AIMS: The objectives of this review are: to know both HMB metabolism and toxicity, and to identify HMB cellular and molecular mechanisms of action when used as a dietary supplement. METHODS: A search was performed in the Web of Science, Pubmed and SportDiscus data bases. RESULTS were divided into two parts; this article presents aspects referring to HMB mechanisms of action. RESULTS: There is insufficient evidence that HMB intake increases muscle cholesterol synthesis. It probably has positive effects on muscle metabolism through both the mTOR and ubiquitin-proteasome pathways, although the mechanism of action is unknown. HMB may increase blood levels of -hydroxybutyrate and this could explain the main effects of HMB on muscle proteolysis. CONCLUSION: According to these results, the possibility of justifying the action of HMB through the beta-hydroxybutyrate pathway opens an interesting line of research for future studies.

Introducción: En los últimos años el -hidroxi--metilbutirato (HMB) ha sido foco de diversas investigaciones que le atribuyen un efecto sobre la disminución de la proteólisis muscular y un incremento de la masa muscular. Por tanto, se han realizado estudios centrados en los mecanismos celulares y moleculares responsables de dichos efectos. Objetivos: Los objetivos de la presente revisión son: conocer el metabolismo del HMB, así como su absorción y excreción; estudiar la posible toxicidad del HMB; e identificar los mecanismos celulares y moleculares de acción del HMB cuando se utiliza como suplemento nutricional. Métodos: Se utilizaron las bases de datos Web of Science, Pubmed y SportDiscus para realizar la búsqueda de artículos. Los resultados se dividieron en dos partes; en este artículo se presentan los resultados referentes a los mecanismos de acción del HMB. Resultados: No existen suficientes datos que apoyen que la ingesta de HMB incremente la síntesis de colesterol en el músculo. Es posible que existan efectos positivos en el metabolismo muscular a través de la vía mTOR y del sistema ubiquitin-proteasoma, aunque no se conoce su mecanismo de acción. Probablemente, el HMB eleva los niveles sanguíneos de hidroxibutirato y esto podría explicar sus principales efectos sobre la disminución de la proteólisis muscular. Conclusiones: De acuerdo a nuestros resultados, la posibilidad de justificar la acción del HMB a través de la vía del beta-hidroxibutirato abre una interesante línea de investigación para futuros estudios.

Effects of leucine and its metabolite ß-hydroxy-ß-methylbutyrate on human skeletal muscle protein metabolism.

Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses-fed gains) in protein turnover. Of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is 'sensed' have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-(13)C2]Leu and [(2)H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A-V) dilution). Orally consumed 3.42 g free-acid (FA-HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling 90 min vs. 30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.

Development and validation of LC-MS/MS method for the estimation of ß-hydroxy-ß-methylbutyrate in rat plasma and its application to pharmacokinetic studies.

A simple, sensitive and specific high-performance liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of ß-hydroxy-ß-methyl butyrate (HMB) in small volumes of rat plasma using warfarin as an internal standard (IS). The API-4000 LC-MS/MS was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. A simple liquid-liquid extraction process was used to extract HMB and IS from rat plasma. The total run time was 3 min and the elution of HMB and IS occurred at 1.48 and 1.75 min respectively; this was achieved with a mobile phase consisting of 0.1% formic acid in a water-acetonitrile mixture (15:85, v/v) at a flow rate of 1.0 mL/min on a Agilent Eclipse XDB C(8) (150 × 4.6, 5 µm) column. The developed method was validated in rat plasma with a lower limit of quantitation of 30.0 ng/mL for HMB. A linear response function was established for the range of concentrations 30-4600 ng/mL (r > 0.998) for HMB. The intra- and inter-day precision values for HMB were acceptable as per Food and Drug Administration guidelines. HMB was stable in the battery of stability studies, viz. bench-top, autosampler freeze-thaw cycles and long-term stability for 30 days in plasma. The developed assay method was applied to a bioavailability study in rats.

Free acid gel form of ß-hydroxy-ß-methylbutyrate (HMB) improves HMB clearance from plasma in human subjects compared with the calcium HMB salt.

The leucine metabolite, ß-hydroxy-ß-methylbutyrate (HMB), is a nutritional supplement that increases lean muscle and strength with exercise and in disease states. HMB is presently available as the Ca salt (CaHMB). The present study was designed to examine whether HMB in free acid gel form will improve HMB availability to tissues. Two studies were conducted and in each study four males and four females were given three treatments in a randomised, cross-over design. Treatments were CaHMB (gelatin capsule, 1 g), equivalent HMB free acid gel swallowed (FASW) and free acid gel held sublingual for 15 s then swallowed (FASL). Plasma HMB was measured for 3 h following treatment in study 1 and 24 h with urine collection in study 2. In both the studies, the times to peak plasma HMB were 128 (sem 11), 38 (sem 4) and 38 (sem 1) min (P < 0·0001) for CaHMB, FASW and FASL, respectively. The peak concentrations were 131 (sem 6), 249 (sem 14) and 239 (sem 14) µmol/l (P < 0·0001) for CaHMB, FASW and FASL, respectively. The areas under the curve were almost double for FASW and FASL (P < 0·0001). Daily urinary HMB excretion was not significantly increased resulting in more HMB retained (P < 0·003) with FASW and FASL. Half-lives were 3·17 (sem 0·22), 2·50 (sem 0·13) and 2·51 (sem 0·14) h for CaHMB, FASW and FASL, respectively (P < 0·004). Free acid gel resulted in quicker and greater plasma concentrations (+185%) and improved clearance (+25%) of HMB from plasma. In conclusion, HMB free acid gel could improve HMB availability and efficacy to tissues in health and disease.

Fragrance material review on cinnamyl formate.

A toxicologic and dermatologic review of cinnamyl formate when used as a fragrance ingredient is presented.

Dietary toxicity of calcium beta-hydroxy-beta-methyl butyrate (CaHMB).

HMB, 3-hydroxy-3-methyl butyrate, is of interest as a dietary supplement and a possible component of functional and medical foods. The purpose of this study was to evaluate the toxicity of the calcium salt of HMB, calcium 3-hydroxy-3-methyl butyrate (CaHMB, monohydrate, food grade), when administered daily in the diet of rats for at least 90 days. Male and female Crl:CD (SD)IGS BR animals were assigned to four groups. Each group received diets containing the carrier or 1%, 2%, or 5% of CaHMB mixed with diet. Assessment of toxicity was based on mortality, clinical observations, body weights, food consumption, and clinical and anatomic pathology evaluations. Administration of CaHMB in basal diet for 91 days was tolerated well. There were no unscheduled sacrifices or deaths. There were no CaHMB-related adverse effects on clinical observations, body weights, food consumption, clinical chemistry, hematology, absolute or relative organ weights, or macroscopic or microscopic observations. A statistically significant increase in inorganic phosphorous was observed in male animals in the 5% feeding group; however, this effect was not considered adverse. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) was considered to be 5% of CaHMB mixed with diet (3.49 g/kg BW for males and 4.16 g/kg BW for females).

Bioconversion of naltrexone and its 3-O-alkyl-ester prodrugs in a human skin equivalent.

The purpose of this study was to compare the percutaneous absorption and bioconversion of naltrexone (NTX), naltrexone-3-O-valerate (VAL), and naltrexone-3-O-(2'-ethylbutyrate) (ETBUT) in a human skin equivalent model (EpiDerm) and in fresh human skin in vitro. NTX diffusion and metabolism to 6-beta-naltrexol (NTXol) were quantitated and compared in the EpiDerm and in excised fresh human skin. VAL and ETBUT diffusion and bioconversion studies were also completed in EpiDerm. Naltrexone bioconverted to levels of 3+/-2% NTXol in the EpiDerm and 1+/-0.5% in fresh human skin. VAL hydrolyzed rapidly in the EpiDerm and mainly (93+/-4%) NTX was found in the receiver compartment, similar to human skin. More intact ETBUT permeated the EpiDerm tissue compared to VAL, and only 15+/-11% NTX was found in the receiver. Significantly higher fluxes of NTX and the prodrugs were observed with the EpiDerm compared to human skin. A similar flux enhancement level was observed for VAL, compared to NTX base, in the EpiDerm and the human skin. Metabolically active human epidermal models like EpiDerm are useful as an alternative experimental system to human skin for prediction of topical/transdermal drug/prodrug bioconversion.

Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design.

Ganciclovir (GCV), a promising antiviral compound, has poor ocular bioavailability as a result of its relatively low partition coefficient. In this study, lipophilic ester prodrugs of GCV were synthesized in an effort to improve its uptake into ocular tissues. In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic mono-acyl ester prodrugs of GCV to determine the effect of lipophilicity and corneal hydrolysis rate on transcorneal diffusion. The GCV prodrugs showed a progressive decrease in solubility and a corresponding increase in Log P values as the chain length was ascended. Permeation studies using freshly isolated rabbit corneas showed that all prodrugs permeated as intact prodrug as well as hydrolyzed GCV. Corneal permeability coefficients increased with increasing lipophilicity for mono-ester prodrugs having more than three carbon atoms in the side chain. The permeability of GCV increased about 6-fold in ascending from the parent drug-ganciclovir (3.82 +/- 0.19 x 10(-6) cm sec(-1)) to its valerate ester prodrug (23.70 +/- 1.36 x 10(-6) cm sec(-1)). Among the prodrugs studied, the valerate ester showed the highest permeability and holds the most potential for development. Overall prodrug permeability correlated linearly with increased susceptibility of the GCV esters to undergo hydrolysis in the cornea. The present work indicates that the ideal prodrug is one that not only possesses enhanced partitioning characteristics, but also high enzyme susceptibility. Concentration of active GCV penetrating the corneal epithelium was substantially increased through the bio-reversible ester prodrug strategy.

Glutathione conjugation of the alpha-bromoisovaleric acid enantiomers in the rat in vivo and its stereoselectivity. Pharmacokinetics of biliary and urinary excretion of the glutathione conjugate and the mercapturate.

The glutathione (GSH) conjugation of (R)-and (S)-alpha-bromoisovaleric acid (BI) in the rat in vivo, and its stereoselectivity, have been characterized. After administration of racemic [1-14C]BI two radioactive metabolites were found in bile: only one of the possible diastereomeric BI-GSH conjugates, (R)-I-S-G (35 +/- 2% of the dose), and an unidentified metabolite "X" (6 +/- 1%). In urine, only one of the possible BI-mercapturates, (R)-I-S-MA (14 +/- 1%), minor unidentified polar metabolites (5 +/- 1%) and unchanged BI (13 +/- 2%) were excreted. When (R) or (S)-BI were administered separately, the same metabolites were found. However, a ten-fold difference in excretion half lives of the biliary metabolites was observed following (S)-and (R)-BI administration, (S)-BI being more rapidly excreted. The excretion of the mercapturate in urine shows the same difference in excretion rate: its half life after administration of (R)-BI was more than 10 times longer than after a dose of (S)-BI. More of the dose of (S)-BI was excreted after 5 hr in bile and urine: 58% and 23% respectively for (S)- and (R)-BI. Therefore, a pronounced stereoselectivity in GSH conjugation exists for the (R) and (S) enantiomers of BI in the rat in vivo, which is a major determinant of their pharmacokinetics. The results suggest that (slow) inversion of the chiral centre of BI occurred in the rat in vivo.

The effect of renal function on the pharmacokinetics of gemfibrozil.

STUDY OBJECTIVE: to determine the effect of renal function on the pharmacokinetics of gemfibrozil following single and multiple oral doses. DESIGN: nonrandomized; paired studies of single versus multiple doses. SETTING: patients enrolled in a veterans hospital renal subspecialty clinic. PATIENTS: 17 male patients 57 to 74 years old selected for various levels of renal function, including end-stage renal disease. INTERVENTIONS: patients initially received 600 mg of oral-gemfibrozil followed by sequential venous blood sampling. Seven to 14 days later, the patients started receiving gemfibrozil, 600 mg bid. Venous blood samples were obtained over the following 10 days and frequently during a 24-hour washout phase. MEASUREMENTS AND MAIN RESULTS: peak gemfibrozil concentrations (mg/L) were 11.1 (3.9 SD) for the single dose and 10.2 (3.8) for the multiple-dose study. Time to peak concentration (hr) was 2.1 (1.0) and 1.8 (0.6), respectively. The mean half-life of elimination (hr) from the single-dose study was 6.4 (11.8) compared with the multidose study of 3.0 (3.1), which did not reach statistical significance (P = .25). The difference between the area under the curve for the single versus the multiple-dose study approached statistical significance (P = .054). The coefficient of determination for creatinine renal clearance versus the plasma clearance of oral gemfibrozil was 0.009 (P = .72) for the single-dose regimen and 0.331 (P = .016) for the multiple-dose study. CONCLUSION: the half-life of gemfibrozil is independent of renal function for both single- and multiple-dose regimens. Dosing schedules do not require alteration for renal insufficiency.