The complexity of Raf-1 regulation.

The activation of the serine/threonine kinase Raf-1 is proving to be an intricate multistep process. Recent advances in elucidating how Raf-1 becomes activated in response to signaling events have emphasized the role of phosphorylation and protein interactions in Raf-1 regulation. The picture clearly emerging is that Raf-1 activity can be regulated by multiple mechanisms.

Regulation of delta protein kinase C during rat ovarian differentiation.

Studies were undertaken to classify protein kinase C (PKC) forms present in rat corpora lutea and to begin to evaluate their regulation during ovarian differentiation. Hydroxyapatite (HAP) column chromatography of rat luteal tissue revealed the presence of multiple forms of PKC (alpha, beta, delta, zeta). Identification of the PKC isoforms was based upon elution positions from HAP column chromatography and immunoreactivity. The delta PKC isoform was identified as the major Ca(2+)-independent form of PKC present in rat luteal tissue. The Ca(2+)-independent, lipid-dependent phosphorylation of the 80-kDa delta PKC was readily detectable in soluble luteal extracts and was shown to reflect autophosphorylation of delta PKC. To evaluate the regulation of PKC isoforms during ovarian differentiation, PKC protein levels were compared between preovulatory follicle-enriched ovaries and corpora lutea obtained on day 16 of pregnancy. Levels of delta PKC protein were greatly elevated in corpora lutea compared to levels in preovulatory follicles. In contrast, levels of alpha and beta PKC protein remained constant while levels of zeta PKC were slightly higher in the follicular than the luteal extract. Levels of delta PKC mRNA were also higher in corpora lutea than in preovulatory follicles. These results are the first to demonstrate the physiological regulation of delta PKC with follicular differentiation into corpora lutea and implicate a role for this prominent PKC form in the corpus luteum during pregnancy.

cAMP-dependent protein kinases in the rat testis: regulatory and catalytic subunit associations.

Based upon recent reports that the rat testis exhibits mRNAs for cAMP-dependent protein kinase (A-kinase) regulatory (R) subunits RI alpha, RI beta, RII alpha, and RII beta, this study was designed to identify R proteins present in extracts of germ cell-rich testis from adult and Sertoli cell-enriched, germ cell-poor testis from 14-15-day-old rats. Following separation by DEAE-cellulose, R subunits were identified by Mr: (a) upon labeling with 8-N3[32P]cAMP and 32P in an RII phosphorylation reaction and; (b) by Western blot analysis using R-specific antibodies on one- and two-dimensional gel electrophoresis. Elution of R subunits as catalytic (C) subunit-free dimers or in association with C subunits to form holoenzyme was determined by their sedimentation characteristics on sucrose gradient centrifugation in conjunction with their cAMP-stimulated activation characteristics on Eadie-Scatchard analysis. Soluble extracts of testes, from both adult and 14-15 day-old rats, showed the presence of a prominent type I holoenzyme containing RI alpha subunits (47 kDa, peak 1), a minor type II holoenzyme, containing RII beta subunits (52 kDa, peak 2), and a second, more abundant, type II holoenzyme peak containing predominantly RII alpha and, to a lesser extent RII beta subunits (peak 3). The 53 kDa RI beta protein predicted by mRNA studies was only tentatively identified by Western blot analysis. Testes extracts of 14-15-day-old, but not adult, rats exhibited high levels of C subunit-free RI alpha, a result not predicted by mRNA studies. This latter result may be attributable to direct RI alpha regulation or to indirect RII beta regulation at a time during testis development prior to germ cell maturation.

Calcium-independent phospholipid/diolein-dependent phosphorylation of a soluble ovarian Mr 80,000 substrate protein: biochemical characteristics.

Soluble ovarian extracts were incubated with protein kinase effectors in the presence of [gamma 32P]ATP and proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Autoradiograms revealed phosphorylation of an ovarian Mr = 80,000 substrate in the presence of EGTA ([ethylenebis(oxyethylenenitrilo)]tetraacetic acid), phosphatidylserine and 1,2-diolein. In contrast to a classical response pattern to C-kinase effectors, the ovarian Mr = 80,000 phosphorylation was inhibited by 2 x 10(-7) M or greater free Ca2+. The ovarian Mr = 80,000 substrate was distinguished from the myristoylated acidic Mr = 80,000 C-kinase substrate of brain tissue on the basis of heat stability and phosphorylative response to effectors. Phosphorylation of the exogenous substrate myelin basic protein by DEAE-resolved ovarian kinase showed the variant effector dependence, maximal in the presence of EGTA, phosphatidylserine and 1,2-diolein. Finally, the effect of Ca2+ on ovarian Mr = 80,000 [32P]phosphate content could not be accounted for by post-phosphorylation activities, or by DEAE-resolvable or hydroxylapatite-resolvable inhibitory activities.

Delta protein kinase-C in the rat ovary: estrogen regulation and localization.

The present studies were undertaken to examine the cellular distribution and regulation of delta protein kinase-C (PKC) at different stages of luteal differentiation in the rat. Results from in situ hybridization studies with a delta PKC-specific probe demonstrated that delta PKC was localized specifically in granulosa cells of healthy preantral, small antral, and preovulatory follicles and corpora lutea from the second half of pregnancy. Northern and Western blot analyses showed that levels of delta PKC protein and messenger RNA were elevated 25- and 35-fold, respectively, in the second half of pregnancy over levels in preovulatory follicle-enriched ovaries, peaking between days 18-20 of pregnancy. Levels of alpha PKC, beta PKC, and zeta PKC remained unchanged during luteal differentiation. In rats hypophysectomized and hysterectomized on day 12 of pregnancy and in immature rats containing corpora lutea induced with PMSG followed by hCG injections, exogenous estrogen caused 3- and 7-fold increases in delta PKC protein, respectively. In the immature rat model, delta PKC messenger RNA levels were not altered by exogenous estrogen. Although exogenous testosterone also elevated delta PKC protein levels, exogenous dihydrotestosterone and progesterone were ineffective. These results suggest that estrogen may participate, at a posttranscriptional level, in the dramatic induction of delta PKC seen at the end of pregnancy in rat corpora lutea.

Effects of probenecid on furosemide kinetics and natriuresis in man.

Furosemide kinetics were studied in 4 normal subjects after single intravenous injections (1 mg/kg). One experiment was done after pretreatment with probenecid. The apparent volume of furosemide distribution was unchanged after probenecid (10.9 L). The mean plasma clearance fell from 155 to 85 ml/min and the mean plasma t1/2 rose from 36 to 61 min. Renal clearance of furosemide fell below 50% of control after probenecid, but the kidney remained the main route of its excretion (75% of the dose appeared in the urine). In another experiment in 4 subjects an infusion of furosemide was sustained following a loading dose to maintain a constant plasma level. After a control period, probenecid was given orally. This resulted in a decrease in renal excretion of furosemide with a simultaneous rise in its plasma concentration. Despite the rising plasma furosemide concentration, however, there was a diminution in both urine flow and the excreted fraction of filtered sodium, which suggested some reduction of diuretic action. In doses commonly used, probenecid reduces renal elimination of furosemide in man with only a mild impairment of its diuretic activity. This suggests that furosemide is eliminated predominantly by way of proximal tubular secretion and that tubular rather than plasma concentration is the main determinant of its diuretic effect.

Phenobarbital--valporic acid interaction.

The effect of subchronic valproate treatment on the single-dose kinetics of phenobarbital was investigated in 6 normal subjects. The study consisted of 2 drug treatments assigned through randomized crossover design. In one treatment subjects received a 60-mg dose of phenobarbital orally. In the other, subjects received 250 mg valproic acid orally twice daily for 14 consecutive days and a 60-mg dose of phenobarbital orally on day 4. Nineteen plasma samples (over 12 days) and two 48-hr urine samples were collected during each treatment. Plasma and urine phenobarbital levels were determined by gas chromatograph interfaced with mass spectrometer in a chemical ionization mode (GLC/CI/MS) and plasma valproic acid levels by GLC. Valproic acid induced several changes in the elimination parameters of phenobarbital: (1) phenobarbital half-life rose from 96 to 142 hr (p = 0.006); (2) plasma clearance fell from 4.2 to 3.0 ml/hr/kg (p = 0.009); (3) renal clearance was unchanged, and metabolic clearance fell from 3.3 to 2.0 mg/hg/kg (p = 0.006); and (4) the fraction of dose excreted unchanged rose from 0.22 to 0.33 (p = 0.015), and the fraction of dose metablized fell from 0.78 to 0.67 (p = 0.015). The findings indicate that valproic acid inhibits phenobarbital metabolism.

Effects of carbamazepine on valproic acid kinetics in normal subjects.

Carbamazepine and valproic acid are used together in the treatment of epilepsy. It is therefore, relevant to investigate the possibility of a carbamazepine effect on valproic acid disposition, particularly since carbamazepine is known to induce enzymes. We gave valproic acid orally to 6 normal subjects, 250 mg twice daily for 4 wk. Carbamazepine, 200 mg once daily, was begun after 4 days on valproic acid. Serum drug concentrations were measured during 4 dosing intervals, once before and 3 times after beginning carbamazepine. Minimum steady-state concentrations of valproic acid declined after carbamazepine from 34.4 +/- 5.1 to 27.1 +/- 4.4 mug/ml (p less than 0.0005). Clearance rose from 6.46 +/- 0.80 to 8.48 +/- 2.28 ml/hr/kg (p less than 0.01). The increase in clearanace and decrease in minimum steady-state levels was apparent only after 2 wk on carbamazepine. The elimination rate constant (KE) during the dosing interval did not rise during carbamazepine administration (0.0623 +/- 0.0168 hr--1 before and 0.0573 +/- 0.0168 hr--1 after, p greater than 0.25), raising the possibility of an increase in distribution volume.

Cefadroxil kinetics in patients with renal insufficiency.

Kinetic parameters and bioavailability of cefadroxil were studied in 20 subjects with differing renal function as measured by endogenous creatinine clearance (CCr). Two subjects were on hemodialysis. After an overnight fast, each subject ingested two 500-mg capsules of cefadroxil. The peak serum concentration was variable (12 to 57 mg/L) and correlated inversely with the CCr. All but one patient had maximum absorption within 4 hr of ingestion and in most patients the peak was reached within the 2-hr sample. Urinary recovery within 48 hr was 45% to 106% when CCr greater than 8 ml/min. Even in patients with the most severe renal failure (CCr less than 10 ml/min), urine concentrations of cefadroxil were adequate to treat susceptible bacteria. The rate of oral absorption ka, was not affected by the state of renal function and was 0.76 +/- 0.50 hr-1. The apparent distribution volume (V d ext) was 0.28 +/- 0.09 L/kg. The plasma elimination rate was dependent on CCr wih a small fraction of drug being removed by nonrenal routes. Except in advanced renal failure, tubular secretion was present since renal clearance of cefadroxil exceeded CCr. The data suggest that little drug accumulation will occur with the usual 8- to 12-hr dosing schedule except when the CCr is less than 25 ml/min.

Time-course of interaction between carbamazepine and clonazepam in normal man.

The applicability of a pharmacokinetic model for drug interactions by enzyme induction was tested by chronic dosing situation using carbamazepine (Tegretol) as the inducer and clonazepam (Clonopin) as the drug affected. Seven healthy subjects received one 1.0 mg clonazepam tablet once a day for 29 days and one 200 mg carbamazepine tablet once a day from days 8 to 29. Plasma levels of clonazepam were measured by electron-capture gas-liquid chromatography and those of carbamazepine and its epoxide metabolite by gas chromatographic-chemical ionization-mass spectrometry. Clonazepam plasma levels reached an initial steady-state by day 7 and declined to a lower steady-state over 5 to 15 days after additions of carbamazepine. The decrease in clonazepam levels ranged between 19% and 37%. Autoinduction of carbamazepine metabolism was also evident. Urinary excretion of D-glucaric acid increased 2- to 4-fold following carbamazepine administration (p less than 0.005). This increase provided additional evidence that the present interaction was due to enzyme induction. Experimental clonazepam levels were fitted to an induction pharmacokinetic model for multiple dosing with an exponentially increasing clearance. Induced half-lives of clonazepam (mean = 22.5 +/- 11.5 hr) were shorter (p less than 0.005) than control values (32.1 +/- 16.6 hr). Apparent enzyme(s) turnover half-lives ranged between 1 and 6 days.

Sotalol kinetics in renal insufficiency.

Kinetics of sotalol, a beta adrenoceptor blocker, was studied in 20 patients with varying renal function. In subjects with creatinine clearance (Clcr) greater than or equal to 39 ml/min/m2, sotalol plasma clearance (x +/- SD) was 71 +/- 31 ml/min/m2, elimination half-life (t 1/2) was 8.1 +/- 3.4 hr, and renal clearance was 46 +/- 26 ml/min/m2. In patients with moderate renal impairment (Clcr = 8 to 38 ml/min/m2) elimination t 1/2 rose to 24.2 +/- 7.5 hr, and plasma clearance fell to 24 +/- 7 ml/min/m2. In patients receiving dialysis, elimination t 1/2 rose to 33.9 +/- 27.1 hr. Elimination t 1/2 during hemodialysis was 5.8 +/- 2.1 hr and was associated with a 56.7 +/- 21% reduction in plasma levels.

Cefonicid kinetics in subjects with normal and impaired renal function.

Cefonicid is a cephalosporin with a longer t1/2 than currently available cephalosporins. Cefonicid kinetics after an intravenous dose of 7.5 mg/kg were followed in four groups of subjects: group 1, four subjects with normal creatinine clearance (Clcr greater than 80 ml/min); group II, seven subjects with mild renal insufficiency (Clcr 50 to 80 ml/min); group III, five subjects with moderate to severe renal impairment (Clcr 8 to 49 ml/min); and group IV, five subjects with end-stage renal disease who were receiving maintenance hemodialysis (Clcr less than 8 ml/ml). Cefonicid volume of distribution ranged from 6.9% to 17.6% body weight but was not related to Clcr. Elimination t1/2 was 4.6 +/- 0.7 hr in group 1,6.0 +/- 2.7 hr in group II, 25.6 +/- 14.0 hr in group III, and 65.3 +/- 43.6 hr in group IV. There was a strong correlation between plasma cefonicid clearance and Clcr. Nonrenal clearance did not change with decreasing Clcr. Hemodialysis clearance calculated from plasma concentrations and recovery in dialysate was 2.5 +/- 0.9 ml/min. These kinetic parameters were used to formulate dosage regimens for patients with renal impairment.

Antihypertensive therapy in the elderly. Effects on blood pressure and cerebral blood flow.

Antihypertensive therapy significantly reduces cardiovascular morbidity and mortality in the rapidly growing population of elderly patients. However, the desire to treat more of these patients is dampened by the concern that a reduction in blood pressure may compromise cerebral blood flow, causing untoward consequences. This study evaluated the therapeutic effect of titrated doses of prazosin, an alpha-adrenergic blocking agent, on systemic blood pressure and cerebral blood flow in elderly patients with chronic stable hypertension. Prazosin alone or co-administered with hydrochlorothiazide significantly lowered mean systolic and diastolic blood pressures in 31 elderly hypertensive patients. At the same time, however, there was no significant change in cerebral blood flow, which was measured in eight patients. Neither harmful biochemical changes nor treatment-related adverse effects were observed in any patients. Prazosin therapy alone or in combination with low-dose diuretic therapy was effective in the treatment of hypertension in this elderly population. Furthermore, blood pressure reduction with prazosin therapy was accomplished without compromising cerebral blood flow and without unfavorably altering lipid profiles.

Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency.

The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat. This metabolite is cleared by both hepatic and renal routes, while most other ACE inhibitors are cleared exclusively by the kidney. In the present study, after administration of multiple fixed oral doses the accumulation of the active moieties of fosinopril, enalapril and lisinopril was compared in patients with renal insufficiency. 29 patients with creatinine clearances (CLCR) less than 30 ml/min received either fosinopril 10mg (n = 9), enalapril 2.5mg (n = 10) or lisinopril 5mg (n = 10) once daily for 10 days in a nonblind (open-label) parallel study. Pharmacokinetic parameters including area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time to peak concentration (tmax), as well as renal function, blood pressure, and plasma renin activity (PRA) and aldosterone levels, were determined on the first and last days of the study. The percentage (+/- SEM) increases in AUC from day 1 to day 10 for fosinoprilat, enalaprilat and lisinopril were 26.8 +/- 9.9 (nonsignificant), 76.6 +/- 16.6 (p less than 0.001) and 161.7 +/- 31.8% (p less than 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p less than 0.05) or lisinopril (p less than 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p less than 0.01). Renal function was not altered in any group, and blood pressure changed modestly.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of blood pressure, plasma lipid and cardiac performance responses to prazosin versus propranolol in thiazide-treated hypertensive patients.

Twenty-seven patients with uncontrolled hypertension (diastolic blood pressure greater than or equal to 95 mm Hg) receiving thiazide diuretics were treated with the addition of either propranolol (n = 10) or prazosin (n = 17). Nine patients were successfully controlled with propranolol and 12 with prazosin. Six patients required both study drugs for optimal blood pressure control, 5 of whom had received prazosin as the initial study drug. Changes in serum lipid components and cardiac performances with the addition of the study drugs were monitored. A decrease in total cholesterol and an increase in high-density lipoprotein (HDL) cholesterol were seen when prazosin was added, and an increase in total cholesterol and a decrease in HDL cholesterol occurred after the addition of propranolol. Although in this small group of patients these changes did not reach statistical significance, they were similar to changes described in other studies in which these drugs were used as monotherapy for hypertension. The only lipid change of statistical significance was a small increase in the serum triglyceride concentration in patients receiving propranolol. The findings for total cholesterol and its fractions suggest that the effects of the study drugs may not be additive to those of thiazides and that thiazides had already effected a maximal lipid response. Both agents in combination with a thiazide diuretic were equally effective in decreasing diastolic blood pressure to the goal of less than or equal to 85 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of PKC delta expression by estrogen and rat placental lactogen-1 in luteinized rat ovarian granulosa cells.

Protein kinase C (PKC) delta is dramatically upregulated in the corpus luteum in the second half of pregnancy in the rat. To gain insight into the hormonal regulation of PKC delta expression, studies were undertaken to analyze the regulation of PKC delta expression in a luteinized rat granulosa cell model. PKC delta protein expression was evaluated in luteinized granulosa cells, isolated from human (h)CG-treated immature female rats 7 h after the injection of an ovulatory dose of hCG and cultured up to 12 days. Cytochrome P450 cholesterol side chain cleavage enzyme expression was observed throughout the culture period, and a majority of the cells expressed steroidogenic acute regulatory protein and responded to rat placental lactogen (rPL)-1 by exhibiting hypertrophy, consistent with maintenance of the luteal phenotype. Both PKC delta protein and mRNA expression increased 3.5-4-fold with time of culture, and PKC delta mRNA expression could be eliminated by treatment of cells with the PKC inhibitor GF109203X. E(2) caused a specific dose- and time-dependent increase in expression of PKC delta protein of twofold, whereas PKC delta mRNA was unaffected by E(2) over a 12-day culture period. Treatment of cells with 500 ng/ml rPL-1 for the final 4 days of a 12-day culture in the absence of E(2) had no effect on PKC delta protein or mRNA expression, while treatment with 500 or 3000 ng/ml rPL-1 in the presence of E(2) significantly enhanced both PKC delta protein and mRNA expression (up to threefold). These results show that two of the major regulators of luteal function in the second half of pregnancy in the rat, E(2) and rPL-1, cooperate to regulate PKC delta expression in luteinized granulosa cells.

Regulation of protein kinase C delta by estrogen in the MCF-7 human breast cancer cell line.

We have previously shown that estrogen up-regulates expression of protein kinase C (PKC) delta in the rat and rabbit corpus luteum as well as in luteinized rat granulosa primary cell cultures. To determine whether a similar regulation of the PKC delta isoform by estrogen occurred in another estrogen responsive system, we investigated the estrogen receptor positive MCF-7 human breast cancer cells. In a characterization of PKC isoforms in MCF-7 cells we determined that PKC delta was the predominant PKC isoform. However in contrast to the effect of estrogen on PKC delta expression in ovarian cells, estrogen treatment of MCF-7 cells resulted in a significant decrease in PKC delta protein and mRNA expression in a time and dose dependent manner. Treatment of MCF-7 cells with 10(-10)-10(-8) M estrogen for 7 days down-regulated specifically PKC delta mRNA and protein while expression of other PKC isoforms was unchanged. The opposite regulation of PKC delta expression in ovarian and breast cancer cells prompted us to evaluate the type of estrogen receptor present in both cell types. Results showed that luteinized rat granulosa cells expressed predominantly estrogen receptor beta while the MCF-7 cells expressed predominantly estrogen receptor alpha and barely detectable levels of estrogen receptor beta. These results suggest that the differential ability of estrogen to regulate PKC beta expression could potentially be a result of differential signaling through the two estrogen receptor subtypes.

Apparent reduced absorption of gemfibrozil when given with colestipol.

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half-life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 +/- 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 +/- 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t-test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 +/- 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 +/- 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half-life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.

Pharmacokinetics of iothalamate in endstage renal disease.

Some nephrologists make alterations in routine peritoneal and hemodialysis schedules after diagnostic studies that use radiographic contrast agents. A study to determine the pharmacokinetics of one contrast agent, iothalamate, is reported. The plasma (total body) clearance of iothalamate was measured in seven patients who had endstage renal disease (ESRD) and who received maintenance hemodialysis. During an interdialytic period, plasma clearance of iothalamate varied from 0.7 to 5.2 mL/min (3.1 +/- 1.8 mL/min, mean +/- SD) with an elimination rate constant (beta) of 0.0164 +/- 0.01 hr-1, a terminal half-life of 61 +/- 42 hours, and an estimated distribution volume of 11 +/- 3.9 L. Hemodialysis clearance of iothalamate was 104 +/- 54 mL/min. With the assumption that iothalamate is mainly distributed in the extracellular fluid (ECF) compartment, the theoretical fluid shift from the intracellular fluid (ICF) compartment to the ECF compartment was 323 mL after administration of the largest dose (2.1 mL/kg or 1.6 mmol/kg of body weight) of 60% meglumine iothalamate solution. The average maximum serum osmolarity change was less than expected, suggesting some type of internal buffering of meglumine iothalamate. In the first few hours after radiocontrast administration in four patients, the average change in serum osmolarity was 5 mmol/L; the average change in serum sodium concentration during this same time was a decrease of 0.5 mmol/L. The minor increase in ECF volume induced by hyperosmolar contrast agents does not require immediate dialysis in most patients. When needed, however, for contrast-related adverse effects, hemodialysis is efficient in rapidly removing iothalamate.

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.