We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN Vancomycin (VAN) has been widely used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. It is mainly eliminated via the kidneys and has a narrow therapeutic range; high doses cause nephrotoxicity, particularly if it is used in combination with an aminoglycoside antibiotic (6, 28). The area under the blood concentration-time curve (AUC)/MIC is the pharmacodynamic parameter that best correlates with a successful outcome after the use of VAN (20,27). Therefore, it is believed that therapeutic drug monitoring (TDM) is appropriate for VAN therapy (3,16,18,29).The initial VAN dosage regimen is usually selected by use of a nomogram that uses the serum creatinine concentration as a marker of renal function. Our previous studies indicated that the nomogram that uses the serum creatinine concentration does not accurately predict the serum VAN trough concentration, particularly in elderly individuals (33). This is probably caused by using the serum creatinine concentration as a marker of renal function because this leads to an overestimation of the glomerular filtration rate (GFR) (17). A more accurate marker of GFR is needed for the appropriate use of VAN because renal function is one of the most important factors affecting the clearance of VAN. It has been reported that the serum cystatin C concentration is a better marker of renal function than the serum creatinine concentration (5). A recent meta-analysis demonstrated that the serum cystatin C concentration is superior to the serum creatinine concentration for use for the detection of an impaired GFR (7). Some studies reported that the serum cystatin C concentration is a better marker of drug clearance than the serum creatinine concentration (15, 23). Recently, we have shown that the serum cystatin C concentration is a better marker for determination of the initial dose in VAN therapy. In a previous study, GFR was estimated on the basis of the serum cystatin C concentration in place of the creatinine clearance, which is the parameter usually used to determine the population pharmacokinetics of VAN (32). However, a means of population pharmacokinetic analysis that uses the serum cystatin C concentration as a marker of renal function is lacking.We approached the population pharmacokinetic analysis of VAN using the serum cystatin C concentration and a onecompartment model for adult patients infected with MRSA. Covariate selection revealed that total body weight (TBW) affected the volume of distribution, whereas renal function (estimated from GFR by use of the serum cystatin C concentration) affected VAN clearance. We also compared the predictive performance of the trough serum VAN concentration for determination of the initial dose with that of the use of the nomogram and the serum creatinine concentration. MATERIA...

To evaluate an in vitro model suitable for investigating intestinal first-pass drug metabolism, CYP3A4 and MDR1 mRNA induction by 1alpha,25-dihydroxyvitamin D(3) (VD3) was examined in two human intestinal cell lines, Caco-2 and LS180, under various culture conditions. CYP3A4 mRNA expression was induced by 100 nM VD3 at levels between 234-549 times above normal in Caco-2 cells for 2 weeks and by 74-200 times above normal in LS180 cells for 2 days. The CYP3A4 induction effect of 250 nM VD3 was similar to or slightly higher than that of 100 nM VD3 in both Caco-2 and LS180 cells. Also, CYP3A4 was induced in Caco-2 and LS180 cells when they were cultured on a polystyrene plate slightly less than when they were cultured on a porous membrane. The increase in fetal bovine serum (FBS) content in the culture medium resulted in little or only slight increase of CYP3A4 induction in both Caco-2 and LS180 cells. MDR1 mRNA expression was marginally increased by VD3 in LS180 cells, but not in Caco-2 cells, and neither increased FBS content nor use of a porous membrane significantly affected MDR1 induction in LS180 cells. The transepithelial electrical resistance of LS180 cells was almost zero, whereas that of Caco-2 cells was high and was marginally decreased by VD3. These findings indicate that Caco-2 cells cultured on a porous membrane with 100 nM VD3 for 2 weeks may be used as a model to investigate the intestinal absorption and first-pass metabolism of drugs, while LS180 cells may be utilized to elucidate the mechanisms which regulate intestinal CYP3A4 mRNA expression.

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, K(m) and V(max) , were examined in the incubation study, the K(m) values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The V(max) values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased K(m) values accompanied the decreased V(max) values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the K(m) value was observed in ARF rats, but it did not accompany the decrease in the V(max) value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats.

The intestinal expression of the CYP3A subfamily was investigated in female rats, and the intestinal metabolism of two CYP3A substrates, testosterone and rifabutin, was examined and compared between males and females. CYP3A1/23 and CYP3A2 intestinal expression was barely detected in male and female rats. Although CYP3A9 was predominantly expressed in the female rat liver, its expression in the intestine was not different between the two sexes. The rate of testosterone 6b b-hydroxylation in the female intestine was similar to that for males. Rifabutin was also metabolized at similar rates in both intestines, although the metabolic rate was greater in the female liver. These results indicate that the intestinal drug metabolizing activity of the CYP3A subfamily is similar between males and females, and that CYP3A9 is involved in the intestinal metabolism of CYP3A substrates in both sexes.

To characterize the intestinal absorption of digoxin, its transcellular transport and drug interaction activity was investigated using Caco-2 cell monolayers. We examined digoxin transport in the presence and absence of ouabain to determine whether digoxin binding to Na ؉ ,K ؉ -ATPase affects its transcellular digoxin transport, and evaluated its influx and efflux clearance by model-dependent pharmacokinetic analysis. Transcellular transport in the basal-to-apical direction was greater than that in the opposite direction. In addition, ouabain decreased the cellular accumulation of digoxin, but it did not alter its transcellular transport profile. The observations for transcellular transport and cellular accumulation in the presence of ouabain were used for the pharmacokinetic analysis, which showed that the efflux clearance of digoxin on the apical side of the monolayer was 15 times greater than that on the basal side. Apical-to-basal transport was increased by carvedilol and pimobendan, and these compounds suppressed the efflux clearance on the apical side and the influx clearance on the basal side. These findings indicate that the intestinal absorption of digoxin is primarily dominated by the efflux process on the luminal side of the intestine, and that carvedilol and pimobendan may vary the rate of intestinal digoxin absorption mainly by inhibiting its exsorptive transport.

The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)). ARF induced a significant increase in blood propranolol concentration after intra-intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg(-1) was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg(-1) dose was 54.7% and 81.4% in control and ARF rats, respectively. In contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first-pass extraction (E(h)) was dose-dependent and saturable: E(h) of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg(-1), respectively, and E(h) in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg(-1), respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism.

A comparative study of altered plasma concentration of quinidine in rats with glycerol- and cisplatin-induced acute renal failure (ARF) was conducted with quinidine used as a positively charged and liver-metabolized therapeutic compound. Although apparent total body clearance of quinidine decreased to 68 and 48% of the normal value in glycerol- and cisplatin-induced ARF rats, respectively, its distribution decreased only in glycerol-induced ARF rats. The plasma unbound fraction of quinidine decreased in glycerol-induced ARF rats, which was not observed in cisplatin-induced ARF rats. The plasma level of alpha(1)-acid glycoprotein (AGP) increased in glycerol-induced ARF, but not in cisplatin-induced ARF rats. It is therefore conceivable that the plasma concentration of positively charged and liver-metabolized compounds generally increases due to hepatic elimination suppressed as renal function decreases, but the pharmacokinetic impact of suppressed hepatic elimination is occasionally difficult to observe in some ARF model rats since it may be blurred by the influence of increased plasma AGP level.

ARF decreases the lithium disposition to CSF, possibly by promoting lithium efflux from CSF due to increased NKCC1 expression in the choroid plexus.