Plasma protein binding of quinine: binding to human serum albumin, alpha 1-acid glycoprotein and plasma from patients with malaria.

The binding of quinine to human serum albumin (HSA), alpha 1-acid glycoprotein (AAG) and plasma obtained from healthy subjects (10 caucasians and 15 Thais) and from Thai patients with falciparum malaria (n = 20) has been investigated. In healthy volunteers, plasma protein binding expressed as the percentage of unbound quinine was 7.9-31.0% (69-92.1% bound). The mean percentage of unbound quinine found with essentially fatty acid-free HSA (40 g L-1) was 65.4 +/- 1.5% (mean +/- s.d.) and was comparable with the value (66.3 +/- 3.8%, mean +/- s.d.) for Fraction V HSA (40 g L-1). This suggests that fatty acids do not influence the plasma protein binding of quinine. Binding of quinine to 0.7 g L-1 AAG was high (mean unbound 61.0 +/- 5.0%), indicating that quinine is bound primarily to AAG and albumin, although other plasma proteins such as lipoproteins may be involved. The mean percentage of unbound quinine was slightly less in caucasians (14.8 +/- 6.7% unbound), compared with healthy Thai subjects (17.0 +/- 6.7% unbound). The higher binding of quinine in caucasian subjects was associated with a higher plasma AAG concentration observed in caucasians. Mean percentage of unbound quinine was significantly lower in Thai patients with malaria (10.9 +/- 4.0%) than in the healthy Thai subjects. The increase in the extent of quinine binding corresponded with the increase in the acute-phase reactant protein, AAG in the patients with malaria. Overall, when the data were combined there was a significant correlation (r = 0.846, P < 0.005) between the binding ratio (bound/unbound) of quinine and the plasma AAG concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma protein binding of d-propoxyphene in normal subjects and anephric patients

The free fraction of d-propoxyphene in the plasma of normal subjects is 0.24 +/- 0.02 (mean +/- S.D.) and is not concentration dependent in the usual therapeutic and toxic conentration range. Renal failure and relatively high concentrations of d-norpropoxyphene, the major metabolite of d-propoxyphene, have no significant effect on the plasma protein binding of d-propoxyphene.     

The passage of flunitrazepam into cerebrospinal fluid in man

The passage of flunitrazepam into cerebrospinal fluid (CSF) was studied in 23 surgical patients (group 1), after a single 0.02 mg/kg intravenous injection, in 9 otherwise healthy patients undergoing neurological examination (group 2), after a single 2 mg oral dose, and in 9 chronically-ill neurological patients (group 3), after 2 to 4 successive 2 mg oral doses. Flunitrazepam in plasma and the CSF was determined by gas chromatography and its plasma protein binding by equilibrium dialysis. Uptake of flunitrazepam into human CSF was found to very fast: even 5 min. after intravenous injection the drug level in the CSF was 2.8% of the corresponding plasma concentration. CSF levels increased up to 77 min. after intravenous injection. In group 2 the mean percentage level in the CSF was 23.5 +/- 13.0 (S.D.) and in group 3 it was 16.7 +/- 3.1. In group 1, 22.9+/- 8.0% of flunitrazepam was not bound to plasma protein, in group 2, 12.1 +/- 8.3% and, in group 3, 30.3 +/- 14.1%. Groups 1 and 2 (P less than 0.01) and 2 and 3 (P less than 0.01) differ significantly from each other. In groups 2 and 3 there was no significant correlation between the percentage not bound to protein and CSF levels of flunitrazepam. The uptake of flunitrazepam by CSF provides an explanation for its rapid drug effects. Its binding to plasma protein is affected by disease and, possible, by other drugs.     

Protein binding of nifedipine

The protein binding of nifedipine in concentrations up to 1200 ng ml-1 has been measured in serum, pure human albumin solution and pure human alpha 1-acid glycoprotein (AAG) solutions by ultrafiltration. The drug was extensively bound in serum from four healthy volunteers with a mean (+/- s.d.) fraction bound of 0.992 +/- 0.008. In albumin solution (40 g litre-1) the mean (+/- s.d.) fraction bound 0.970 +/- 0.012, was not significantly different (P greater than 0.05) from that in serum, suggesting that albumin is the major, but not necessarily the only, binding protein for nifedipine in serum. The binding of nifedipine in solutions of AAG was proportional to the AAG concentration and ranged from 0.514 +/- 0.059 to 0.755 +/- 0.035 in solutions containing 50 and 150 mg % AAG, respectively. Binding of nifedipine in all protein solutions was linear.     

Distribution of 7-hydroxymethotrexate in human blood

We have examined the in-vitro distribution of 7-hydroxymethotrexate (7-OH-MTX), a cytotoxic metabolite of methotrexate (MTX), in human blood, and its protein binding in serum. The distribution of 7-OH-MTX (10(-6) M) in fresh samples of whole blood was studied at 37 degrees C and pH 7.51 +/- 0.05 (mean +/- s.d.), and its protein binding was assessed by equilibrium dialysis of serum against Krebs Ringer phosphate buffer at 37 degrees C and pH 7.41 +/- 0.07 (mean +/- s.d.). 7-OH-MTX had a mean cell/plasma concentration ratio of 0.03 (range 0-0.27, n = 18). It was extensively bound in human serum, with a bound fraction of 90.4 +/- 3.3% (mean +/- s.d.) in healthy volunteers (n = 11), and significantly lower, 82.3 +/- 4.0% (mean +/- s.d.), in hypoalbuminaemic surgical patients (n = 7). The binding of 7-OH-MTX was correlated with serum albumin (HSA) concentrations (r = 0.72, P less than 0.0007, n = 18). Blood distribution data support the contention that 7-OH-MTX has a small volume of distribution, and HSA appears to be mainly responsible for the high degree of its protein binding in serum.     

Pharmacokinetics, N1-glucuronidation, and N4-acetylation of sulfa-6-monomethoxine in humans

Sulfamonomethoxine (S) is metabolized by O-dealkylation, N4-acetylation, and N1-glucuronidation. In humans, only N1-glucuronidation (12%) and N4-acetylation (36%) takes place. The N1-glucuronide is directly measured by HPLC. When N4-acetylsulfamonomethoxine (N4) is administered as the parent drug, N1-glucuronidation does not occur. After an oral dose, fast and slow acetylators show a similar t1/2 for S (25.0 +/- 4.6 hr vs. 29.8 +/- 4.8 hr; p = 0.459), and the t1/2 of the N4-acetyl conjugate is also similar in fast and slow acetylators (25.0 +/- 4.64 hr vs. 29.8 +/- 4.8 hr, p = 0.459). The intrinsic mean residence time of N4 is 7.1 +/- 2.3 hr. The mean total body clearance of S is 5.0 +/- 1.3 ml/min, the renal clearance is 0.84 +/- 0.26 ml/min, and the volume of distribution at steady state is 11.7 +/- 3.4 liters. The renal clearance of N4 is 17.89 +/- 4.19 ml/min. No measurable concentrations of the N1-glucuronide of S are found in plasma. The protein binding of S is 92%. N1-glucuronidation results in an 80% reduction in the protein binding of S (11%). N4 shows a high protein binding of 98%. Approximately 60% of the oral dose of S is excreted in the urine.     

Plasma concentrations and pharmacokinetics of dihydralazine after single oral doses to human subjects

After single oral doses of 20 mg of a suspension of dihydralazine sulphate to human subjects, the peak of mean plasma concentrations of dihydralazine of 47.0 ng ml-1 +/- 11.0 standard deviation (S.D.) (n = 7) was reached at 1 h. Mean concentrations declined biphasically with apparent half-lives of 0.57 and 4.96 h respectively. Dihydralazine was partly converted to hydralazine. The peak of mean plasma concentrations of the latter drug of 3.9 ng ml-1 +/- 1.7 S.D. (n = 7) occurred at 1-2 h after dosing with dihydralazine sulphate and declined to 1.5 ng ml-1 +/- 1.5 S.D. at 6 h. Of the seven subjects studied, three were classified as fast and four as slow acetylators. Mean clearances appeared to be slightly more rapid in fast acetylators (1.63 l min-1 +/- 0.32 S.D.) when compared to slow acetylators (1.31 l min-1 +/- 0.31 S.D.) but this difference and differences in plasma concentrations and in areas under the plasma drug concentration-time curves were not significant (p > 0.1).     

The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in man

[14C]-N-Ethoxycarbonyl-3-morpholinosydnonimine (molsidomine, Corvaton) was administered orally at a dose of 2 mg per subject to eight healthy male volunteers. Maximal plasma concentrations of total radioactivity of 32.4 +/- 6.4 ng equiv./ml (mean +/- S.D.) were detected compared with maximum plasma concentrations of 14.1 +/- 5.9 ng/ml (mean +/- S.D.) of molsidomine. In both cases these were attained at 0.5 h after dosing. From the peak, concentrations of parent drug fell rapidly with a half-life of 1.25 +/- 0.38 h (mean +/- S.D.). In contrast, total radioactivity declined more slowly with a terminal half-life of 138 +/- 42.7 h (mean +/- S.D.). The bulk of the radiolabel was rapidly excreted as metabolites in the urine, with over 85% of the dose recovered in the first 24 h. The main urinary radiolabelled metabolites appeared, from chromatographic evidence, to be similar to those previously identified in animals, namely N-morpholinosydnonimine, N-cyanomethylamino-N-(2'-hydroxyethyl)glycine and (N-cyanomethylenamino-2-aminoethoxy)-acetic acid.     

Protein binding of oxazepam and its glucuronide conjugates to human albumin

The binding of oxazepam and its glucuronide conjugates to human serum albumin (HSA), as well as the binding interactions of the drug and its metabolites, were examined by equilibrium dialysis and kinetic probe studies. Oxazepam and its S(+) glucuronide are bound to the HSA molecule with affinity constants of 3.5 X 10(5) M-1 and 5.5 X 10(4) M-1, respectively, which were independent of protein concentration over a range of 0.1 to 5.0 g/dl. The R(-) glucuronide bound weakly to albumin, with the binding parameter, N X K, increasing at lower albumin concentrations. Pre-acetylation of fatty acid free-HSA resulted in decreased binding of all three compounds, probably by altering the conformation of the binding sites. Kinetic probe studies with p-nitrophenyl acetate indicate that oxazepam and its S(+) glucuronide shared a common binding site on HSA, but that the R(-) glucuronide bound at another site. Oxazepam binding was unaffected by the presence of its glucuronide conjugates but was inhibited by fatty acids. The percentage of oxazepam bound to plasma proteins in patients with renal impairment (94%) was lower than in normal volunteers (97%). This lower binding can neither be attributed to lower albumin concentrations because of the large binding capacity of the protein and linearity of N X K nor to displacement by elevated concentrations of glucuronide conjugates, but it may be ascribed partly to increased plasma fatty acids.     

Distribution of moricizine in human blood: binding to plasma proteins and erythrocytes.

Using equilibrium dialysis and incubation experiments, we determined the binding of moricizine to human plasma, isolated plasma proteins, and erythrocytes. The mean (% +/- SD) plasma protein binding at various moricizine concentrations ranged from 81.2 +/- 2.1 to 89.9 +/- 2.1%. There was no apparent relationship between drug concentration and extent of binding in pooled plasma over the concentration range tested. However, protein concentration-dependent binding was observed with albumin and alpha 1-acid glycoprotein (alpha 1-AGP). The unbound fraction of moricizine fell from 61 to 19% and from 70 to 17% with increasing albumin (5 and 50 g/L, respectively) and alpha 1-AGP (0.2 and 1.2 g/L) concentrations. The binding of moricizine to beta-lipoprotein (5 g/L) was 70.6 +/- 3.1% and to gamma-globulin (12 g/L) was 13.6 +/- 3.3%. Moricizine partitioned into erythrocytes, showing an erythrocyte/plasma drug concentration ratio of 1.325 +/- 0.070 and erythrocyte/buffer ratio of 8.561 +/- 0.620. An estimation could be made that 57% of total drug in whole blood was associated with erythrocytes, 39% bound to plasma proteins, and 4% was free. The results of this study demonstrated that erythrocytes, albumin, and alpha 1-AGP were the major binding components in blood.     

Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone

The effects of caffeine on the in-vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated. Caffeine failed to decrease in-vitro protein binding of ceftriaxone. Rabbit plasma concentrations of ceftriaxone (30 mg kg-1 i.v.) were elevated significantly (P less than 0.05 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg-1 i.v. was co-administered compared with ceftriaxone given alone. Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 +/- 38 ml kg-1 (mean +/- s.d., n = 6) to 97 +/- 33 ml kg-1 (caffeine 5 mg kg-1, P less than 0.05), and 94 +/- 8 ml kg-1 (caffeine 10 mg kg-1, P less than 0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 +/- 106 ml kg-1 (mean +/- s.d., n = 6) to 31 +/- 18 ml kg-1 (caffeine 5 mg kg-1, P less than 0.5) and 36 +/- 31 ml kg-1 (caffeine 10 mg kg-1, P less than 0.1). The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P less than 0.05) after caffeine. The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.     

Stereoselective interactions of ketoprofen glucuronides with human plasma protein and serum albumin.

A clearance pathway common to many aryl alkanoic acids is the generation of renally eliminated ester glucuronides. These metabolites are susceptible to systemic hydrolysis which generates the parent aglycone. We have conducted in vitro studies with biosynthetic R- and S-ketoprofen glucuronides to elucidate the mechanism of this phenomenon. These conjugates were incubated in human plasma, various concentrations of human serum albumin (HSA) and protein-free buffer. It was apparent that albumin, rather than plasma esterases, catalysed the hydrolysis of the glucuronides. The albumin-catalysed hydrolysis of ketoprofen glucuronides was highly stereoselective. The mean (+/- SD) hydrolysis half-life of R-ketoprofen glucuronide in plasma (N = 4) at physiological pH and temperature was 1.37 (+/- 0.30) hr. The corresponding value for S-ketoprofen glucuronide, 3.46 (+/- 0.84) hr, was significantly different (P less than 0.005). In contrast, synthetic ethyl esters of R- and S-ketoprofen were hydrolysed by plasma esterases, but not by HSA, and with little stereoselectivity. The reversible protein binding of ketoprofen glucuronides was determined at physiological pH and temperature by a rapid ultra-filtration method. The binding of R- and S-ketoprofen glucuronide to human plasma protein was independent of concentration (P greater than 0.05) over the range of 1-20 micrograms/mL. The mean (+/- SD) percentage unbound in plasma (N = 4) of R-ketoprofen glucuronide was 12.6 (+/- 1.4)%. The corresponding value for S-ketoprofen glucuronide, 9.12 (+/- 0.54)%, was significantly different (P less than 0.005). S-Ketoprofen glucuronide was also more avidly protein bound in physiological concentrations of HSA. However, this stereoselectivity decreased in more dilute HSA solutions. Based on the hydrolysis and protein binding data for ketoprofen glucuronides, we propose the existence of separate binding and catalytic sites on the albumin molecule for these metabolites.     

Iodide concentrations in matched maternal serum, cord serum, and amniotic fluid from preterm and term human pregnancies

OBJECTIVES: To characterize the matched maternal and cord plasma and the amniotic fluid concentrations of iodide in preterm and term human pregnancies. METHODS: Specimens were collected at the delivery of 121 singleton pregnancies (92 at term, 29 preterm) with no pre-existing medical complications. Plasma unbound iodide concentrations were measured by the difference between the protein bound iodine and the total iodine measured spectrophotometrically. Total iodide was measured in amniotic fluid. RESULTS: Maternal plasma iodide concentrations were 1.6 +/- 0.4 mcg/dL (mean +/- S.D.) for preterm deliveries and 1.5+/ -0.5 mcg/dL for term deliveries. Cord plasma iodide concentrations were 1.4 +/- 0.5 mcg/dL for preterm deliveries and 1.7 +/- 0.7 mcg/dL for term deliveries. Cord plasma iodide concentrations at birth correlated highly with maternal levels (p < 0.001). The cord:maternal plasma iodide ratio for all pairs was 1.2+/- 0.7. The average cord:maternal plasma iodide ratio was not significantly different between the preterm (0.9+/- 0.4) and term (1.3+/- 0.8) deliveries. Amniotic fluid iodide concentrations did not correlate significantly with cord plasma concentrations. CONCLUSION: Cord plasma concentrations of iodide correlate with paired maternal levels, indicating that, unlike the rabbit and other species, the human conceptus does not highly concentrate iodide.     

Drug-protein conjugates--V. Sex-linked differences in the metabolism and irreversible binding of 17 alpha-ethinylestradiol in the rat

Sex-linked differences in the disposition, biotransformation, excretion and irreversible binding of [6, 7-3H]17 alpha-ethinylestradiol [( 3H]EE2) in Wistar rats have been observed. Three hours after i.v. administration of [3H]EE2 (5 micrograms/kg) the livers of males contained twice as much 3H-labelled material as those of females. The biliary metabolites were largely glucuronides in both sexes, but males also excreted arylsulphates. The principal metabolites liberated from biliary conjugates by enzymes were 2-hydroxyEE2 and 2-methoxyEE2 in females and males, respectively. Biliary elimination of 3H over 3 hr was slightly greater in males (P less than 0.05). Radiolabelled material was irreversibly bound to hepatic microsomal and soluble protein. The material bound to microsomes represented 0.24 +/- 0.07% (mean +/- S.D.) of the dose in males and 0.56 +/- 0.10% in females (P less than 0.001). Oxygenation of the steroid D-ring was not indicated, and 2-hydroxyEE2 appears to be the precursor of the reactive metabolite. The metabolic basis of the sex-linked difference in irreversible binding is discussed.     

Characterization of chloroquine plasma protein binding in man.

Chloroquine protein binding was determined by equilibrium dialysis of purified plasma proteins and plasma samples from 20 healthy subjects and 14 patients with rheumatoid arthritis. The mean binding was 61 +/- 9% in plasma from healthy subjects (range 46-74%) and 64 +/- 7% in plasma from rheumatoid arthritis patients (range 55-79%). Albumin and alpha 1-acid glycoprotein at physiological concentrations bound chloroquine to an approximately equal extent. Protein binding is unlikely to be an important determinant of chloroquine pharmacokinetics or response.     

Plasma protein binding of frusemide in liver disease: effect of hypoalbuminaemia and hyperbilirubinaemia.

The binding of frusemide was studied in the plasma of 20 healthy subjects and 45 patients with liver disease. The unbound percentage (mean +/- s.d.) of frusemide was 1.64 +/- 0.21 healthy subjects) and 2.24 +/- 0.79 (patients) (P less than 0.01). By grouping the patients on the basis of plasma albuminaemia and bilirubinaemia four clusters namely: 'normal concentrations of albumin and bilirubin' (A), 'hyperbilirubinaemia and normal albumin concentration' (B), 'hypoalbuminaemia and normal bilirubin concentration' (C) and 'hypoalbuminaemia and hyperbilirubinaemia' (D) were defined. The unbound percentage of frusemide was 1.80 +/- 0.36 in (A); 2.44 +/- 1.05 in (B); 2.23 +/- 0.38 in (C); 2.76 +/- 0.77 in (D). The figure for healthy volunteers was not different from A, whereas it was significantly lower than those for B and D (P less than 0.01) and for C (P less than 0.05). A lowered binding of frusemide was associated with hypoalbuminaemia or hyperbilirubinaemia.     

Plasma protein binding of celecoxib in mice, rat, rabbit, dog and human

The plasma protein binding of celecoxib was determined for animals and humans using in vitro and ex vivo methods. Eight, healthy, human volunteers (three male, five female, 20-39 years) received celecoxib (600 mg) BID for 7 days, blood samples were collected and concentrations of bound and unbound celecoxib determined. The fraction of bound drug in the volunteers was constant (97.4 +/- 0.1%) at total celecoxib plasma concentrations ranging from 0.01 to 4.02 microg/mL. The ex vivo plasma protein binding of celecoxib in the animals was concentration-independent up to approximately 12, 8 and 10 microg/mL for mouse, rat and dog, respectively. The plasma protein binding of celecoxib after a single oral dose of 10 and 300 mg/kg to mice was 98.3 +/- 0.2%, of 1 and 400 mg/kg to rats was 98.3 +/- 0.2% and of 1 and 100 mg/kg to dogs was 98.5 +/- 0.1%. The percent binding of celecoxib to plasma proteins in vitro was slightly lower than those values determined ex vivo. The in vitro binding of celecoxib to plasma protein was constant over the concentrations of 0.1-10 microg/mL for all species, except rat.     

Relative bioavailability of trimeprazine tablets investigated in man using HPLC with electrochemical detection

The stability, partition coefficient, plasma protein binding, red blood cell distribution, and whole blood concentrations of trimeprazine were investigated. Trimeprazine solution was stable for 6 months at -20 degrees C and 3.5 months at 40 degrees C. In whole blood trimeprazine was stable for 5 weeks at -20 degrees C, 24 h at 4 degrees C, 4 h at 25 degrees C and 1 h at 37 degrees C. The apparent hexane-water partition coefficient varied from 1.50 (at pH 4.83) to over 100 (at pH 10.54). The fraction bound to plasma protein exceeded 0.9 as estimated by equilibrium dialysis with correction for volume shift. The mean plasma/red blood cell concentration ratio was 1.17 and the mean red blood cell/plasma distribution coefficient was 8.65. Six healthy adult males received single 5 mg doses of trimeprazine in a syrup (5 mg in 10 ml) and tablets with at least two weeks between doses. Blood was collected for 48 h. The mean (+/- s.e.m.) times for peak blood concentrations were 3.5 +/- 0.22 h for the syrup and 4.5 +/- 0.43 h for the tablets. There were no significant differences in Cmax values. The overall mean (+/- s.e.m.) terminal phase half-life was 4.78 +/- 0.59 h. Mean (+/- s.e.m.) areas under the concentration time curves from 0 to infinity (AUC infinity) were 11.0 +/- 1.99 ng h-1 ml-1 and 7.67 +/- 1.05 ng h-1 ml-1 for syrup and tablets, respectively. The mean relative bioavailability for the tablets was approximately 70% with respect to the syrup.     

Reversible binding of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid to plasma proteins and its distribution into blood cells in various species

The plasma protein binding and distribution in blood cells of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) has been investigated in-vitro using filtration and an HPLC method to measure DMXAA. DMXAA (500 microM) was extensively bound in plasma from all species with an unbound fraction (fu) of 4.61+/-1.10 (mouse), 2.59+/-0.32 (rat), 2.02+/-0.48 (rabbit) and 2.07+/-0.23% (human). The binding was concentration dependent with DMXAA concentrations > or = 1,000 microM markedly increasing the fu in the plasma from all species. The estimated number of binding sites in plasma were 2.4+/-0.2 (mouse), 1.7+/-0.2 (rat), 0.8+/-0.1 (rabbit) and 2.1+/- 0.2 (human). The major binding protein in human plasma was albumin, with negligible binding to gamma-globulin and alpha1-acid glycoprotein. There was a significant linear relationship between the bound:free DMXAA concentration ratio (Cb/Cu) and albumin concentration in human serum albumin solution (r = 0.955; P < 0.05) and in healthy human plasma (r = 0.998; P< 0.05), but not in plasma from cancer patients (n = 5), nor across species. In cancer patients (n = 5) DMXAA had a significantly higher (P < 0.05) fu (4.60+/- 0.42%) compared with healthy human plasma (2.07+/-0.23%). In human plasma, the fu of DMXAA (500 microM) was significantly reduced by 500 microM diazepam (P < 0.05), but not by warfarin, phenylbutazone, salicylic acid, ibuprofen or clofibric acid at that concentration. DMXAA significantly reduced the binding of dansylsarcosine (a Site-II binder) to HSA, but significantly increased the binding of dansylamide (a Site-I binder). Within species, the blood:plasma concentration ratio (CBL/CP) of DMXAA was relatively constant (mouse, 0.581+/-0.005; rat, 0.667+/-0.025; rabbit, 0.637+/-0.019; human, 0.673+/-0.103) over the range 50-1000 microM, but increased significantly at DMXAA concentrations > 1000 microM in all species except the rabbit. These results indicate that significant alterations in DMXAA plasma binding and distribution into blood cells occur with increasing concentrations of DMXAA in all species, and also that significant interspecies differences exist. It would be more appropriate to compare plasma unbound concentrations when assessing DMXAA exposure in cancer patients or when extrapolating across species.     

Lack of effect of cimetidine on the pharmacokinetics of R(-)- and S(+)-ibuprofen.

1. To investigate the effect of cimetidine on the pharmacokinetics of R(-)- and S(+)-ibuprofen, six healthy male volunteers received orally 800 mg racemic ibuprofen both in the drug-free state (control phase, C) and on the second day of a 3 day course of oral cimetidine, 1 g daily (treatment phase, T). The two phases (14 days apart) were randomised in a balanced cross-over manner. 2. The plasma concentrations of R(-)- and S(+)-ibuprofen were measured by high-performance liquid chromatography (h.p.l.c.). The protein binding of the enantiomers was assessed in a selection of plasma samples from each volunteer. Following alkaline hydrolysis of glucuronide conjugates, the urinary recoveries of ibuprofen and its major metabolites were measured by h.p.l.c. 3. There was no difference (P greater than 0.05, two-tailed Student's t-test; data expressed as mean +/- s.d.) between C and T phases in the total area under the plasma concentration-time curve of R(-)-ibuprofen (C 4514 +/- 1063 mg 1(-1) min vs T 4665 +/- 1435 mg 1(-1) min) and S(+)-ibuprofen (C 6460 +/- 1063 mg 1(-1) min vs T 6886 +/- 1207 mg 1(-1) min). Similarly, for each enantiomer, there was no difference between the two phases in the terminal half-life, the maximum plasma concentration or the time of its occurrence. 4. Cimetidine treatment had no effect (P greater than 0.05) on the time-averaged percent unbound in plasma of R(-)-ibuprofen (C 0.419 +/- 0.051% vs T 0.435 +/- 0.060%) and S(+)-ibuprofen (C 0.643 +/- 0.093% vs T 0.633 +/- 0.053%). (ABSTRACT TRUNCATED AT 250 WORDS)