Tobramycin Serum Concentrations After Aerosol and Oral Administration in Cystic Fibrosis

We sought to describe tobramycin absorption after aerosol administration to cystic fibrosis (CF) subjects. Serum tobramycin concentrations were determined by modification of the radioimmuno-assay (RIA) technique, lowering the limit of detection from 1.0 &mgr;g ml(minus sign1) to 0.05 &mgr;g ml(minus sign1). In 37 studies, after aerosol delivery of 666 plus minus 195 mg to the airway of 24 patients, in which 222 samples were assayed, only 1 serum sample contained tobramycin at a concentration greater than 1.0 &mgr;g ml(minus sign1). Twenty-six of the 37 studies permitted estimation of pharmacokinetic parameters of tobramycin. The serum clearance of tobramycin following aerosol adminstration is 39.13 plus minus 0.393 L h(minus sign1) (mean plus minus standard error of the mean), with an elimination half-life of 3.072 plus minus 0.194 h. The half-life was significantly longer than that found after intravenous adminstration. The elimination rate constant (K(e)) was calculated to be 0.234 plus minus 0.002 h(minus sign1). Estimated total-body clearance in which systemic absorption was determined from sputum and urinary recovery of tobramycin was 0.094 plus minus 0.002 1 hr(minus sign1) kg(minus sign1). We also studied tobramycin absorption in six CF subjects after ingestion of a 80-mg m(minus sign2) dose, to gain insight into the tobramycin levels observed after swallowing an aerosol. Four out of the six subjects had measurable serum tobramycin concentration after ingestion. The serum concentration-time curve mirrored what was seen after aerosol administration. We concluded that tobramycin has poor systemic absorption in CF subjects after aerosol administration. Tobramycin in serum after aerosol administration is in part due to the gastrointestinal absorption of swallowed drug, as well as absorption from lower respiratory tract.     

Pharmacokinetics in Non-Insulin-Dependent Diabetics of the Aldose Reductase Inhibitor, Zopolrestat

The pharmacokinetics of zopolrestat have been examined in non-insulin-dependent diabetic patients after oral administration of a single dose of 1000 mg zopolrestat. T(max) ranged from 2 to 4 h with a mean C(max) of 100 &mgr;g ml(minus sign1). Mean plasma half-life of zopolrestat was 26.9 h. The same patients were also administered oral doses of 1000 mg day(minus sign1) for 10 consecutive days. Mean T(max) was 4.3 h and mean C(max) was 208 &mgr;g ml(minus sign1). Plasma accumulation, the ratio of AUC((0--24)) for the last dose to AUC((0--24)) for the first dose, was 2.67. Apparent oral clearance was 5.71 ml min(minus sign1) and apparent volume of distribution was 12.9 L. The mean urinary excretion of unchanged drug over the 24-h period following the last dose was 36% of the dose while another 7% of the dose appeared in the urine as an acylglucuronide of zopolrestat. Renal clearance of zopolrestat was 1.82 ml min(minus sign1). Binding of zopolrestat to plasma proteins exceeded 99% and was concentration dependent.     

The Influence of Misoprostol on the Adverse Renal Effects and Stereospecific Pharmacokinetics of Ibuprofen in Chronic Renal Insufficiency

The use of nonsteroidal anti-inflammatory drugs in patients with chronic renal insufficiency (CRI) may be complicated by renal functional abnormalities due to the inhibition of renal prostaglandins. We tested the hypothesis that administration of the oral PGE1 analog, misoprostol, could attenuate the adverse renal effects of ibuprofen in patients with CRI. Because the metabolism of misoprostol and the stereoinversion of R- to S-ibuprofen involve the same metabolic pathway, the stereospecific pharmacokinetics of ibuprofen were also evaluated. In a randomized, crossover trial of six stable CRI patients (Clcr 25--67 ml min(minus sign1)), in sodium balance on a 150 mEq Na(+) per day metabolic diet, we compared the effects of ibuprofen 600 mg qid with and without misoprostol 200 &mgr;g qid upon Clcr, Clinulin, Clpah, Na(+), and K(+) excretion during 4-h clearance studies. We also assessed stereospecific ibuprofen kinetics following single dose (acute) and after 7 days on drug(s) (chronic). Daily weights, supine blood pressures, electrolytes, osmolality, BUN, creatinine and 24-h urine collections for Clcr and Na(+) and K(+) excretions were obtained during chronic dosing. Supine and upright plasma renin activities were obtained prior to dosing and during chronic dosing for both treatment limbs. Ibuprofen alone resulted in an approximately 20% transient reduction in GFR, occurring 2--2.5 h following dosing in both the acute and chronic clearance studies. This was not affected by misoprostol. There was a greater degree of stimulation of PRA with the upright posture with misoprostol plus ibuprofen than with ibuprofen alone. There was a significant weight gain in both study limbs, but no effect of misoprostol (1.2 plus minus 0.2 kg ibuprofen alone and 1.0 plus minus 0.2 kg ibuprofen plus misoprostol, p = 0.13). Otherwise no clinically significant alteration in renal function occurred in either treatment limb. The presence of misoprostol did not alter the stereospecific pharmacokinetics of ibuprofen. We conclude that misoprostol does not significantly alter the renal effects of ibuprofen in patients with mild to moderate CRI.     

Effects of Different Doses of Acetylsalicylic Acid on Renal Function in the Dog

This study was carried out in order to examine the effect of increasing doses of intravenously administered lysine-acetylsalicylic acid (ASA) on renal function in dogs. The first purpose was to examine the acute effects on renal water and solute output. The second purpose was to correlate the para-aminohippuric (PAH) clearance measurements with measurement of renal PAH extraction and renal blood flow (RBF). After 7 mg/kg ASA (20–80 μg SA/ml plasma) a decrease in sodium excretion was observed in all dogs. With increasing ASA doses, the urine sodium excretion declined to 23 % of the control period excretion. Tubular reabsorption of free water increased 10%. A significant and dose-related decrease in PAH clearance was observed in all dogs, from 108.7 ml/min after 7 mg/kg ASA to 58.8 ml/min after 200 mg/kg ASA. The creatinine clearance was unchanged. PAH extraction fell in all dogs. RBF (measured by flowmeter) decreased 21 % at the highest plasma SA levels, as compared with 46 % decrease in PAH clearance. ASA seems to inhibit tubular transport of PAH. Inhibition of prostaglandin synthesis by ASA offers one explanation of the effects on RBF and sodium excretion.     

Pharmacokinetics and Pharmacodynamics of Recombinant Human Insulin-Like Growth Factor

Recombinant human insulin-like growth factor (rhIGF-I) was evaluated in 18 healthy males to determine its effects on serum glucose, its relationship of total IGF levels to serum glucose response and dose proportionality when administered intravenously (IV) and subcutaneously (SQ). One group of six subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, 1 week apart, and three groups of four subjects received 60, 120, and 180 &mgr;g kg(minus sign1) IV over 8 h, and then 1 week later received 60, 120, and 90 &mgr;g kg(minus sign1) SQ of rhIGF-I, respectively. During each dosing period, placebo and then rhIGF-I was administered on two consecutive days. Intravenous and subcutaneous does of rhIGF-I demonstrated significant decreases in glucose levels as compared to placebo that did not correspond to peak total IGF levels. Sequential repeat administration of IV infusions of rhIGF-I in a single group of subjects demonstrated significant dose-dependent increases, whereas single administration of the doses in three groups of subjects failed to demonstrate dose dependency for either the IV or subcutaneous routes of administration. These findings suggest that saturation of the binding proteins and sites occurred at the lowest dose (60 &mgr;g kg(minus sign1)) evaluated.     

Misoprostol and Prednisone Treatment of Lupus Nephritis

Fourteen patients were enrolled in a placebo-controlled double-blind randomized trial of 8 weeks of treatment for active lupus nephritis. Seven patients received prednisone at a dose of 1 mg kg(minus sign1) day(minus sign1) plus misoprostol at a dose of 200 &mgr;g P.O. Q.I.D.; 7 patients received prednisone plus placebo. The patients included 12 females, 2 males; 3 African-Americans, 3 Asians, 5 Hispanics, and 3 Caucasians. There were no serious side effects associated with prednisone or misoprostol treatment during the 8-week study period. Laboratory measures obtained at baseline, 4, 8, and 12 weeks included complete blood count (CBC), ESR, C reactive protein (CRP), serum creatinine, creatinine clearance, 24-h urine protein excretion, C3, C4, and anti-double stranded DNA (anti-dsDNA). Statistical analysis was conducted assessing change in measures over time in the entire study group by paired t-tests. The effect of treatment on change over time was examined by analysis of covariance. Log transformation of the variables was performed prior to statistical analysis. For the entire study group, the mean levels of ESR, CRP, 24-h protein excretion, C3, C4, and anti-dsDNA were improved at 4, 8, and 12 weeks. The mean ESR at baseline was 70 plus minus 8 compared to 42 plus minus 8 at 12 weeks (p < 0.01). The mean CRP at baseline was 0.6 plus minus 0.2 compared to 0.2 plus minus 0.1 at 12 weeks (p < 0.01). The 24-h protein excretion was 4367 plus minus 769 mg at baseline compared to 2512 plus minus 709 mg at 12 weeks (p = 0.02). The mean C3 at baseline was 40 plus minus 4 mg dl(minus sign1) compared to 60 plus minus 4 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean C4 at baseline was 14 plus minus 1 mg dl(minus sign1) compared to 23 plus minus 2 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean anti-dsDNA at baseline was 4268 plus minus 1780 compared to 316 plus minus 111 at 12 weeks (p < 0.001). The baseline serum creatinine (1.12 plus minus.15 mg dl(minus sign1)) and creatinine clearance (82 plus minus 15 ml min(minus sign1)) were not significantly changed at 12 weeks (1.10 plus minus 0.2 mg dl(minus sign1) and 80 plus minus 17 ml min(minus sign1), respectively). Comparing the misoprostol treatment group to the placebo group, there were no statistically significant differences for ESR, CRP, creatinine, creatinine clearance, 24-h protein excretion, C3, C4, or anti-dsDNA at any time points. However, comparing the misoprostol treatment group at 4 weeks to the placebo group, a more rapid decrease in anti-dsDNA (reduction of 3297 plus minus 2374) was observed in the misoprostol treatment group versus 304 plus minus 409 in the placebo group), as well as lower mean anti-dsDNA levels (464 plus minus 140) in the misoprostol treatment group versus 4118 plus minus 3834 in the placebo group). Also, the C3 and C4 levels at 12 weeks in the misoprostol treatment group (67 plus minus 5 and 27 plus minus 3 mg dl(minus sign1), respectively) were greater than levels in the placebo group (52 plus minus 4 and 19 plus minus 3 mg dl(minus sign1), respectively). The data demonstrate that oral prednisone is effective in reducing proteinuria and improving the biological markers of disease activity (i.e., ESR, CRP, C3, C4, and anti-dsDNA) following short-term treatment of active lupus nephritis. Additionally, the more rapid change in anti-dsDNA levels and superior normalization of complement levels in the treatment group, although not statistically significant, are consistent with a biologic effect of misoprostol on lymphocyte function and the production of a pathogenic autoantibodies.     

Effect of Food on the Pharmacokinetics and Pharmacodynamics of Torsemide

The effect of food on the bioavailability, pharmacokinetics, and pharmacodynamics of oral torsemide was examined in a group of 14 healthy male volunteers. Administration of torsemide with a standard high-fat, high-carbohydrate breakfast resulted in a decrease in absorption rate (fed: C(max) 988 plus minus 269 ng ml(minus sign1), T(max) 1.50 plus minus 0.64 h; fasting: C(max) 1466 plus minus 202 ng ml(minus sign1), T(max) 0.89 plus minus 0.37 h) but no change in the extent of absorption (fed: AUC 3424 plus minus 841 h ng ml(minus sign1); fasting: AUC 3357 plus minus 859 h ng ml(minus sign1)) or the amount of drug excreted unchanged (fed: % dose 23.5 plus minus 4.3; fasting: % dose 23.7 plus minus 6.2). Elimination half-life and renal clearance were unchanged. These minor alterations in the pharmacokinetics of the drug were not reflected by a change in either the pharmacodynamic relationship between urinary sodium and drug excretion rates or the cumulative amount of electrolytes and urine excreted. The diuretic effect of torsemide will be consistent regardless of drug administration relative to food intake.     

Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers

The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19--38 years) and in 12 geriatric volunteers (65--76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1--3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1--4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The T(max) for ceftibuten and ceftibuten-trans occurred at about 2 and 3 h, respectively, in both populations. The C(max) and AUC((0--12 h)) ranged from 10.8 to 12.4 &mgr;g ml(minus sign1) and from 47.5 to 55.1 &mgr;g h ml(minus sign1), respectively, for normal volunteers compared to 12.9--17.5 &mgr;g ml(minus sign1) and 62.3--87.1 &mgr;g h ml(minus sign1), respectively, for geriatric volunteers. The respective values for ceftibuten-trans in normal and geriatric volunteers were 1.3 and 1.3 &mgr;g ml(minus sign1), respectively, and 6.9--8.2 and 5.9--9.8 &mgr;g h ml(minus sign1). At steady state, the C(max) and AUC((0--12 h)) of ceftibuten-trans were about 10--11% and 13--16% those of ceftibuten in normal volunteers and about 8--9% and 9--11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.     

Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes

BACKGROUND: CYP2C9 polymorphisms are associated with decreased S-warfarin clearance and lower maintenance dosage. Decreased expression of VKORC1 resulting from the -1639G>A substitution has also been implicated in lower warfarin dose requirements. We investigated the additional contribution of this polymorphism to the variance in warfarin dose. METHODS: Sixty-five patients with stable anticoagulation were genotyped for CYP2C9 and VKORC1 with Tag-It allele-specific primer extension technology. Plasma S-warfarin concentrations and warfarin maintenance dose were compared among patients on the basis of the VKORC1 -1639G>A genotype. RESULTS: Eighty percent of CYP2C9*1/*1 patients stabilized on <4.0 mg/day warfarin had at least 1 VKORC1 -1639A allele. Mean warfarin doses (SD) were 6.7 (3.3), 4.3 (2.2), and 2.7 (1.2) mg/day for patients with the VKORC1 -1639GG, GA, and AA genotypes, respectively. Steady-state plasma concentrations of S-warfarin were lowest in patients with the VKORC1 -1639AA genotype and demonstrated a positive association with the VKORC1 -1639G allele copy number (trend P = 0.012). A model including VKORC1 and CYP2C9 genotypes, age, sex, and body weight accounted for 61% of the variance in warfarin daily maintenance dose. CONCLUSIONS: The VKORC1 -1639A allele accounts for low dosage requirements of most patients without a CYP2C9 variant. Higher plasma S-warfarin concentrations corresponding to increased warfarin maintenance dosages support a hypothesis for increased expression of the VKORC1 -1639G allele. VKORC1 and CYP2C9 genotypes, age, sex, and body weight account for the majority of variance in warfarin dose among our study population.     

Effects of different doses of acetylsalicylic acid on renal function in the dog.

This study was carried out in order to examine the effect of increasing doses of intravenously administered lysine-acetylsalicylic acid (ASA) on renal function in dogs. The first purpose was to examine the acute effects on renal water and solute output. The second purpose was to correlate the para-aminohippuric (PAH) clearance measurements with measurement of renal PAH extraction and renal blood flow (RBF). After 7 mg/kg ASA (20-80 microgram SA/ml plasma) a decrease in sodium excretion was observed in all dogs. With increasing ASA doses, the urine sodium excretion declined to 23% of the control period excretion. Tubular reabsorption of free water increased 10%. A significant and dose-related decrease in PAH clearance was observed in all dogs, from 108.7 ml/kg ASA to 58.8 ml/min after 200 mg/kg ASA. The creatine clearance was unchanged. PAH extraction fell in all dogs, RBF (measured by flowmeter decreased 21% at the highest plasma SA levels, as compared with 46% decrease in PAH clearance. ASA seems to inhibit tubular transport of PAH. Inhibition of prostaglandin synthesis by ASA offers one explanation of the effects of RBF and sodium excretion.     

A Nonparametric Alternative to Modeling Population Pharmacokinetics in Patients with Spinal Cord Injury: Comparison with the Standard Two-Stage Method

The estimation of population-specific pharmacokinetic parameters from sparse of fragmentary data obtained during routine patient care is a powerful analytical tool in drug development and therapeutic drug monitoring. The Nonparametric Expectation Maximization program (NPEM) performs this function and generates robust parameter estimates which are distribution-free and unconstrained by assumption-rich parametric, for example, Gaussian, analyses. We compared standard two-stage method (STS) estimates of amikacin pharmacokinetic parameters (V, CL) derived from a sampling rich strategy (11 patients with spinal cord injury, SCI; 7 able-bodied controls) to estimates of pharmacokinetic parameters obtained from an NPEM one-compartment analysis incorporating the 11 optimally sampled SCI patients and 8 sparse data sets (19 patients with SCI; 7 controls). The STS (n = 11) and NPEM (n = 19) analyses provided similar V and CL parameter estimates in patients with SCI: 0.20 plus minus 0.04 L kg(minus sign1), 0.93 plus minus 0.24 ml min(minus sign1) kg(minus sign1) and 0.20 plus minus 0.06 L kg(minus sign1), 1.12 plus minus 0.26 ml min(minus sign1) kg(minus sign1), respectively. NPEM is a useful, user-friendly, distribution-free computational program for estimating the central tendency and interindividual variability of amikacin pharmacokinetic parameters in spinal cord injured humans.     

The effect of fimasartan, an Angiotensin receptor type 1 blocker, on the pharmacokinetics and pharmacodynamics of warfarin in healthy korean male volunteers: a one-sequence, two-period crossover clinical trial

BackgroundFimasartan is an angiotensin II receptor antagonist used to treat hypertension.ObjectiveThe aim of this study was to evaluate the effects of fimasartan on the pharmacodynamics and pharmacokinetics of warfarin in healthy volunteers to meet regulatory requirements for drug marketing and labeling in Korea.MethodsAn open-label, 1-sequence, 2-treatment, 2-period crossover study was conducted in healthy male volunteers. The subjects were administered a single-dose of warfarin 25 mg on day 1. After a 7-day washout period, once-daily fimasartan 240 mg was administered every morning from day 8 to day 16. On day 11, warfarin 25 mg was administered concomitantly with fimasartan. Serial blood samples were collected for 144 hours after each warfarin dose. The plasma concentrations of R- and S-warfarin were analyzed by using HPLC-MS/MS, and the pharmacokinetic parameters were estimated by using noncompartmental analysis. The maximal international normalized ratio (INR) and the AUC–INR curve were evaluated to assess warfarin pharmacodynamics. Tolerability was assessed via vital sign measurements, physical examinations, ECGs, clinical laboratory tests, and adverse events.ResultsA total of 15 healthy Korean men aged 20 to 39 years (mean [SD], 26.7 [5.1] years) and weighing 60.2 to 85.7 kg (mean, 71.4 [8.3] kg) participated in the study; 12 completed the study. The geometric mean ratios (GMRs [90% CIs]) of C_max and AUC_0–last for R-warfarin were 1.06 (0.97–1.16) and 1.07 (1.03–1.12), respectively. For S-warfarin, the GMRs (90% CIs) of C_max and AUC_0–last were 1.02 (0.94–1.11) and 0.99 (0.94–1.04). The INR values reached 1.93 (0.31) and 1.96 (0.37) at 36 hours and decreased to <1.2 at 144 hours after warfarin treatment alone and coadministered with fimasartan, respectively. The GMRs (90% CIs) of the maximal INR and AUC–INR curve were 1.01 (0.97–1.05) and 0.98 (0.96–1.01). One (7.7%) of the 13 subjects reported epistaxis during treatment with warfarin alone, and 2 (16.7%) of 12 subjects receiving the combination treatment experienced headache, skin erosion, and an increase in blood creatine phosphokinase. No subjects had an elevated INR >4 or reported any symptoms related to hypotension, including fainting or dizziness.ConclusionMultiple doses of fimasartan did not seem to alter the pharmacodynamics or pharmacokinetics of warfarin in this small, select population of healthy male volunteers. ClinicalTrials.gov identifier: NCT00923533.     

A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy

The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.     

A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation

Aims. Low-dose acetylsalicylic acid (ASA; aspirin) for secondary prevention reduces cardiovascular disease mortality risk. ASA acetylates cyclooxygenase in the portal circulation and is rapidly (half-life, 20 min) hydrolyzed. Certain patients with cardiovascular disease may exhibit high on-therapy platelet reactivity as a result of high platelet turnover, a process whereby platelets are produced and are active beyond the duration of antiplatelet coverage provided by once-daily immediate-release (IR) ASA. A once-daily, extended-release (ER) ASA formulation using ER microcapsule technology was developed to release ASA over the 24-h dosing interval and reduce maximal plasma concentrations to spare peripheral endogenous endothelial prostacyclin production. Methods. Healthy adults (n = 50) were randomized in a crossover study to receive two different ER-ASA single doses (up to 325 mg) and two different IR-ASA single doses (up to 81 mg) in four periods, each separated by ≥14 days. Pharmacodynamics was assessed by measuring serum thromboxane B₂ (TXB₂), urine 11-dehydro-TXB₂, and arachidonic acid-induced platelet aggregation. Pharmacokinetics was determined for ASA and salicylic acid (SA). Results: Both formulations produced dose-dependent inhibition on all pharmacodynamic parameters. Marked inhibition of TXB₂ and 11-dehydro-TXB₂ was maintained over the 24-h dosing interval after a dose of ≥81 mg ER-ASA or ≥40 mg IR-ASA. The dose required to achieve 50% of maximum TXB₂ inhibition with ER-ASA was 49.9 mg versus 29.6 mg for IR-ASA, for a similar maximum pharmacodynamic effect (98.9% TXB₂ inhibition). This suggests that an approximately twofold greater ER-ASA dose (162.5 mg) is necessary to obtain the same response as that of IR-ASA 81 mg. Peak ASA concentrations were lower and T_max was longer with ER-ASA versus IR-ASA. Administration of IR-ASA resulted in a dose-normalized mean C_max of ASA that was approximately sixfold higher than that for ER-ASA and a C_max of SA approximately two- to threefold higher than that for ER-ASA. Conclusion. Both ASA formulations showed dose-dependent antiplatelet activity. Compared with the IR-ASA, ER-ASA released active drug more slowly, resulting in prolonged absorption and lower systemic drug concentrations, which is expected for an ER (24-h) formulation.     

Decreased warfarin clearance associated with the CYP2C9 R150H (*8) polymorphism

The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We conducted a pharmacokinetic study to examine whether the CYP2C9*8 allele impacts warfarin clearance in African-American patients. We also conducted an in vitro kinetic study of S-warfarin 7-hydroxylation using complementary DNA (cDNA)-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and a 25% lower R- to S-warfarin plasma concentration ratio in patients with the CYP2C9*8 allele (n = 12) as compared to CYP2C9*1 homozygotes (n = 26). Consistent with these findings, the in vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein as compared to the wild-type protein. These data show that the R150H variant protein expressed by the CYP2C9*8 allele is associated with lower S-warfarin clearance. This finding provides clinical and experimental evidence to explain the lower warfarin dose requirements in patients with the CYP2C9*8 allele.     

Initial Studies on the Effect of Inhaled Misoprostol in a Guinea Pig Model of Allergic Bronchoconstriction

Inhaled E series prostaglandins (PGEs) have been shown to modulate responses to both allergic and nonallergic provocation. Little is known about the effect of inhaled misoprostol on the airway and whether its antiasthmatic activity would be similar to other PGEs. In the present study, nebulized solutions of misoprostol and PGE(2) (0.3--300 &mgr;g ml(minus sign1)) effectively blocked the acute bronchospasm due to inhaled antigen challenge in actively sensitized guinea pigs. A 300-&mgr;g ml(minus sign1) solution nebulized for 10 s (about 0.25 ml), 5 min prior to challenge, provided nearly complete inhibition with significant reductions seen at 30 and 3 &mgr;g ml(minus sign1) in certain experiments. Misoprostol treatment resulted in a significant reduction in the number of eosinophils present in bronchoalveolar lavage 24 h after antigen challenge. This combination of effects suggests that inhaled misoprostol may be effective in the treatment of the acute and chronic symptoms of asthma.     

Effects of salicylate vs. aspirin on renal prostaglandins and function in normal and sodium-depleted dogs

The effects of aspirin (acetylsalicylate) (ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) on renal prostaglandin (PG) biosynthesis and function have been studied extensively. In contrast, the in vivo effects of a nonacetylated salicylate (SA), such as sodium SA, on renal function have not been well characterized. No studies have examined the effects of SA on renal function in a situation in which the maintenance of normal kidney function is dependent upon intact renal PG synthesis (i.e., sodium restriction-elevated plasma renin activity). To evaluate the effects of SA vs ASA and/or a NSAID, normal and sodium-restricted anesthetized dogs were treated with SA and then meclofenamate (MECLO) or ASA followed by MECLO. In the normal animals, SA significantly decreased renal PGE2 and PGF2 alpha excretion. After SA a significant amount of MECLO-suppressible PGE2 and PGF2 alpha synthesis remained intact. Compared to SA, with ASA there was a greater decrease in PG excretion, with no further decrease in PG excretion with subsequent MECLO treatment. In the sodium-restricted animals (plasma renin activity, 18-24 ng of angiotensin l/ml/hr) ASA decreased PGE2 excretion but SA did not. In these animals SA did not cause renal vasoconstriction. Additional groups of sodium-restricted animals were studied with extremely high doses of ASA and SA (90 mg/kg) to elevate plasma SA to 200 to 250 micrograms/ml. In these animals SA did decrease PGE2 excretion significantly, but only to levels seen typically in normal animals and, after SA, a large amount of PGE2 excretion could be suppressed by MECLO.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single- and Multiple-Dose Pharmacokinetics of Reduced Metabolite (MDL 74,156) following Oral Administration of Dolasetron Mesylate to Normal Male Subjects

Dolasetron, a 5-hydroxytryptamine(3) receptor antagonist, is under investigation for prevention of nausea and vomiting due to chemotherapy. The keto-reduced metabolite of dolasetron has been identified in human plasma and is likely responsible for the antiemetic activity. This study evaluated single and multiple dose pharmacokinetics of the reduced metabolite following oral administration of dolasetron mesylate in healthy male subjects. Five groups (six active/two placebo each) of subjects received either oral doses of dolasetron mesylate ranging from 25 to 200 mg or placebo on day 1 and every 12 h on days 2 through 9. Because plasma dolasetron concentrations were low and sporadic, pharmacokinetics of the parent compound could not be determined. The reduced metabolite appeared rapidly in the plasma and reached a maximal plasma concentration in about 1 h. The maximal plasma concentrations and areas under plasma concentration--time curves were proportional to the dose. The mean apparent oral clearance ranged from 9.89 to 23.10 ml min(minus sign1) kg(minus sign1). The half-life ranged from 5.20 to 10.80 h. Mean renal clearance and fraction of dose excreted in urine were 0.97 to 3.97 ml min(minus sign1) kg(minus sign1) and 7.47 to 31.9%, respectively. The pharmacokinetics of reduced metabolite appears to be dose independent after single and multiple dosing.     

Comparison of Plasma Protein Binding of Basic Drugs in Black and White Individuals

Interethnic difference in drug disposition is an important contributing factor to interindividual variation in drug response. Since interethnic differences in the protein binding of drugs may contribute to variation in drug disposition between ethnic groups, we conducted a study in 10 black Americans (A) and mean (plus minusSE) age 26 plus minus 6 years and weight 80 plus minus 9 kg matched against 10 white Americans (C) with a mean age of 28 plus minus 6 years and weight 81 plus minus 9 kg, all within 10% of ideal body weight. Serum alpha-1-acid glycoprotein (AGP) and albumin concentrations were measured using the auramine-O and bromcresol green methods, respectively. Verapamil, propranolol, lidocaine, disopyramide and diazepam binding in plasma were measured with the equilibrium-dialysis method, involving the determination of free and unbound drug concentrations. The unbound fraction of diazepam (A = 1.1 plus minus 0.1%; C = 1.1 plus minus 0.1%), verapamil (A = 9.5 plus minus 0.8%; C = 9.8 plus minus 0.4%), propranolol (A = 14.2 plus minus 1.0%; C = 12.6 plus minus 0.7%), lidocaine (A = 28.5 plus minus 2.1%; C = 25.7 plus minus 1.1%) and diphenhydramine (A = 42.9 plus minus 10.2; C = 30.4 plus minus 7.01%) showed no significant ethnic differences (unpaired t-test). Disopyramide measured at 7 different concentrations (1.0--20.0 &mgr;g/ml) was similar in both groups, as were the plasma concentrations of AGP (A = 100 plus minus 20 mg 100 ml; C = 120 plus minus 20 mg 100 ml) and albumin (A = 4.3 plus minus 0.1 g 100 ml; C = 4.5 plus minus 0.1 g 100 ml). It is therefore concluded that there are no interethnic differences in the protein binding of basic drugs between black Americans and white Americans and that it is not a major contributing factor to any possible interethnic variation in the disposition of responsiveness of these drugs.     

Selective inhibition of warfarin metabolism by diltiazem in humans

Healthy men were administered i.v. racemic warfarin, S-warfarin or R-warfarin on two occasions, once in the drug-free state and once during concomitant administration of oral diltiazem 120 mg three times daily. Blood samples for determination of plasma warfarin and diltiazem concentrations, the prothrombin time and complete urine collections were obtained for determination of urinary excretion of dehydrowarfarin, 4'-hydroxywarfarin, 6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin and unchanged parent drug for 216 h after each dose. Concurrent diltiazem administration decreased total racemic warfarin clearance (+/- S.D.) [3.60 +/- 0.99 (control) versus 3.19 +/- 0.86 (diltiazem) ml/min; P less than .05]. Disposition of the more potent anticoagulant S-warfarin was not altered by diltiazem treatment. In contrast total clearance of R-warfarin was decreased [3.47 +/- 1.10 (control) versus 2.77 +/- 0.92 ml/min; P less than .05]. No change in the area under the prothrombin time versus time after warfarin administration curve was associated with diltiazem treatment for any warfarin trial. Inhibition of R-warfarin by diltiazem was regioselective for metabolites as determined by fractional clearance of urinary metabolites. R-6-hydroxywarfarin clearance (+/- S.E.) [29.5 +/- 7.2 (control) versus 15.7 +/- 2.8 ml/h; P less than 0.05] and R-8-hydroxywarfarin clearance [21.1 +/- 3.6 (control) versus 11.2 +/- 2.0 ml/h; P less than .05] were selectively decreased with no significant change in the urinary clearance of R-dehydro, R-4-hydroxy and R-7-hydroxywarfarin. Urinary clearance of unchanged R-warfarin was also decreased during diltiazem administration. Diltiazem inhibits warfarin disposition in humans in a stereospecific and regiospecific manner.