PubMed Health⌕ Search

Biomedical subjects

A J McLachlan

Publications and source records attributed to A J McLachlan.

At least 19 recordsLinked to original sources
PubMed1998

Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach.

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(trough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

Administration, Oral↗
PubMed1998

Effect of clofibrate on the chiral disposition of ibuprofen in rats.

A potentially clinically important interaction has been described between clofibrate and ibuprofen in vitro. To determine whether this in vitro interaction is paralleled by a change in pharmacokinetics of ibuprofen in vivo two groups of rats were treated orally with clofibrate (n = 8, 280 mg/kg/day) or vehicle (n = 7) for 3 days. On day 3, 2 hr after the last dose of clofibrate, the rats were given an i.v. dose of pseudoracemic ibuprofen (20 mg/kg, 10 mg R-ibuprofen, 10 mg 13C-S-ibuprofen). Plasma concentrations of the enantiomers were monitored by a stereospecific gas chromatography mass spectrometry assay. The clearance of R-ibuprofen more than doubled in the clofibrate-treated group (mean +/- S.E.M.; 29.4 +/- 4.0 ml/min) as compared to control rats (13.0 +/- 1.4 ml/min; P = .003). This increase was similarly reflected in the clearance by inversion (treated, 23.2 +/- 3.2 ml/min, untreated, 10.0 +/- 1.2 ml/min; P = .003) and there was also an increase in the rate of inversion (treated, t1/2 inversion, 8.3 +/- 1.6 min; untreated, 13.9 +/- 1.4 min; P = .029). By contrast, the estimates of fractional chiral inversion were not affected by clofibrate and were in close agreement whether estimated by the area under the plasma concentration-time curve approach (treated, 0.79 +/- 0.02; untreated, 0.72 +/- 0.02) or by deconvolution (treated, 0.78 +/- 0.02; untreated, 0.73 +/- 0.02). There was a significant increase in volume of distribution at steady-state (treated, 4.42 +/- 1.12 liter/kg; untreated, 1.03 +/- 0.30 liter/kg; P = .017) observed for the R-enantiomer but not the S-enantiomer (treated, 1.04 +/- 0.13 liter/kg; untreated, 1.10 +/- 0.21 liter/kg). Pretreatment of rats with clofibrate significantly increased the concentrations of ibuprofen in fat, lung, brain and liver tissue. With respect to the protein levels of two key enzymes involved in chiral inversion, clofibrate pretreatment significantly induced expression of long chain acyl-coenzyme A synthetase, although the expression of the epimerase was unaltered. It is concluded, that clofibrate may increase the proportion of R-ibuprofen incorporated into long-lived lipid ("hybrid" lipid) stores.

Animals↗
PubMed1997

Pharmacokinetics and tissue distribution of cisplatin and conjugates of cisplatin with carboxymethyldextran and A5B7 monoclonal antibody in CD1 mice.

The plasma disposition kinetics and tissue distribution of platinum was evaluated following intravenous bolus administration to CD1 immune-competent mice of cisplatin, cisplatin conjugated to anti-CEA monoclonal antibody A5B7 via a carboxymethyl dextran (CMdextran) carrier molecule, and cisplatin coupled to the CMdextran in the absence of antibody. In addition, the in vivo characteristics of 125I-labeled A5B7 were compared with and without conjugation to CMdextran. Conjugation of cisplatin [clearance (CL = 0.62 mL/min/g, volume of distribution at steady-state (Vdss) = 16 mL/g] to CMdextran restricted its tissue distribution (Vdss = 0.43 mL/g) and reduced its systemic clearance (CL = 0.055 mL/min/g). Subsequent conjugation of the complex to A5B7 further reduced both its distribution (Vdss = 0.20 mL/g) and clearance (CL = 0.016 mL/min/g). Clearance of A5B7 (CL = 0.002 mL/min/g) was increased by conjugation to CMdextran (CL = 0.014 mL/min/g); tissue distribution was unchanged. A5B7-CMdextran-cisplatin was relatively stable in plasma and other tissues, except the liver. The extent of distribution of platinum into tissues (lung, liver, muscle, kidney) was markedly influenced by conjugation, with the influence being greatest for unmodified cisplatin and least for the A5B7-CMdextran conjugate. However, the time courses of tissue distribution, expressed in mean residence time scales, were similar, implying a common mechanism controlling tissue uptake.

Animals↗
PubMed1997

Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients.

AIMS: To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients. METHODS: Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/C[SS trough]), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/C(SS trough) was calculated for each patient before and after simvastatin administration. RESULTS: The mean fu increased by 29%, from 1.40 +/- 0.1% (mean +/- s.d.) to 1.82 +/- 0.22% after simvastatin administration (P < 0.01). Mean trough concentrations of cyclosporine in whole blood were 349 microg l-1 before and 242 microg l-1 after simvastatin administration (P < 0.0001). The mean cyclosporine daily dosage was 2.87 mg kg-1 and 2.33 mg kg-1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/C(SS trough) was significantly increased from 24.5 l h-1 before to 28.9 l h-1 after simvastatin administration (P < 0.05). Furthermore the median increase in cyclosporine DR/C(SS trough) was 18 l h-1 (-3.1 to 42.1 l h-1, interquartile range). CONCLUSIONS: Cyclosporine fraction unbound and clearance are increased following co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.

Adult↗
PubMed1996

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects.

1. Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week. 2. The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase. 3. The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50 mg to 600 mg day-1, with a weak indication of saturation at the higher 900 mg day-1 dose rate. 4. The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid Emax model and the C50 values for oxypurinol were 26.38 +/- 4.87, (mean +/- s.d.) 36.58 +/- 8.36 and 24.61 +/- 9.08 microM, respectively. 5. 1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C50 for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar. 6. The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C50, was lower than those often observed in clinical practice.

Adult↗
PubMed1996

Pharmacokinetics of fluconazole in people with HIV infection: a population analysis.

1. The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration-time data (between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation (13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection. 2. A one-compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P-PHARM computer programs. 3. The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h-1 and 47.61, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model-dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P-PHARM were in close agreement. 4. Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4 + T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates. 5. Fluconazole clearance (estimated using NONMEM) in subjects with a CD4 + T-lymphocyte count less than and greater than 200 cells mm3 was 0.73 l h-1 (95% CI; 0.64-0.82 l h-1) and 0.99 l h-1 (95% CI; 0.86-1.12 l h-1), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL (l h-1) = 0.25 (33%) + 0.0057 (32%) x CLcr (in ml min-1) + 0.00068 (10%) x CD4 cell count (in cells mm-3) where intersubject variability (expressed as %CV) is shown in brackets. 6. Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.

Adult↗
PubMed1995

Membrane permeability and lipophilicity in the isolated perfused rat liver: 5-ethyl barbituric acid and other compounds.

The distribution kinetics of 5-ethyl barbituric acid (EBA) has been examined in the rat liver. The isolated in situ liver (n = 4) was perfused at a constant rate (15.1 +/- 0.2 ml/min, mean +/- S.D.) with protein-free Krebs bicarbonate medium in a single-pass mode. [14C]Sucrose (extracellular reference) and [14C]EBA were injected separately as bolus doses into the portal vein. The outflow data were analyzed using the axial dispersion model. The one-compartment dispersion model adequately described the data for sucrose, with a dispersion number (DN) of 0.25 +/- 0.04 and a volume of distribution (VH) of 0.14 +/- 0.01 ml/g liver. The two-compartment dispersion model, which incorporates a cellular permeability barrier, provided a better description of the EBA outflow data. The estimated VH, influx and efflux rate constants and permeability-surface area product (PS) for EBA were 0.37 +/- 0.04 ml/g liver, 0.028 +/- 0.004 sec-1, 0.019 +/- 0.001 sec-1 and 3.4 +/- 0.5 ml/min, respectively. Despite low hepatocyte membrane permeability, the DN value for EBA (0.28 +/- 0.03) was not significantly different from that of sucrose, which supports the concept that dispersion of compounds in the liver is primarily determined by the heterogeneity of the hepatic microvasculature. The relationship between PS values in the perfused rat liver (either abstracted or taken from the literature data) and physicochemical properties for 17 compounds has been explored. There appears to be a continuous relationship between PS and logD, a measure of lipophilicity that takes into account the degree of ionization in the perfusate. The PS value for EBA is close to that expected based on its physicochemical properties.

Animals↗
PubMed1994

Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate.

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (-)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration-effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease.

Arthritis, Rheumatoid↗
PubMed1994

Disposition and absorption of hydroxychloroquine enantiomers following a single dose of the racemate.

The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (-)-(R)-hydroxychloroquine exceed those of (+)-(S)-hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (-)-(R)-hydroxychloroquine were higher than (+)-(S)-hydroxychloroquine after oral dosing (121 +/- 56 and 99 +/- 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half-life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (-)-(R)- and (+)-(S)-hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution.

Absorption↗
PubMed1994

Distribution kinetics of salicylic acid in the isolated perfused rat liver assessed using moment analysis and the two-compartment axial dispersion model.

The distribution kinetics of salicylic acid in the single-pass isolated perfused rat liver has been investigated under varying conditions of perfusate flow (15 to 30 ml min-1) and of salicylate perfusate concentration (0, 100, 200 mg l-1) using statistical moment analysis and the two-compartment axial dispersion model. Salicylic acid was not metabolised during the experiment. The perfusate did not contain binding protein. As flow rate was increased, the maximum fraction output per second (f(t)max) increased and the mean transit time (MTTH) decreased, while tmax became shorter for both tritiated water and 14C-salicylic acid. Increasing the salicylate perfusate concentration profoundly affected the frequency outflow profile of 14C-salicylic acid, but not that of tritiated water. The one-compartment axial dispersion model adequately described the frequency outflow profile for tritiated water, whereas the two-compartment form, which incorporates a cellular permeability barrier, provided a better description of the 14C-salicylic acid outflow data. The estimated two-compartment axial dispersion model parameters for 14C-salicylic acid, DN, the dispersion number (0.08 +/- 0.03), k12, the influx rate constant (0.56 +/- 0.04 sec-1) and k21, the efflux rate constant (0.095 +/- 0.01 sec-1) were independent of perfusate flow rate. The in situ permeability-surface area product for 14C-salicylic acid (4.6 +/- 0.7 ml min-1g-1 liver) was in good agreement with literature estimates obtained from in vitro hepatocyte experiments, suggesting that the permeability barrier is at the hepatocyte membrane. Whereas DN and k12 were uninfluenced by, k21 displayed a positive correlation with, salicylate perfusate concentration. This correlation was most likely due to decreased intracellular salicylate binding.

Animals↗
PubMed1994

Bioavailability of hydroxychloroquine tablets in patients with rheumatoid arthritis.

Nine patients with RA received two doses of 155 mg racemic hydroxychloroquine each, as a tablet and by i.v. infusion, in a randomized cross-over design study. Blood concentrations over the first 32 h following each dose were determined. Bioavailability was estimated using a sequential exponential least squares deconvolution method. The mean fraction absorbed from the tablet was 0.79 (range 0.39 to 1.27). The mean absorption lag-time was 1.3 h (range 0.5 to 3.7 h) and the mean time for 50% absorption was 4.3 h (range 1.9 to 10.3 h). Mean rate and extent of hydroxychloroquine absorption were not significantly different from that previously reported for healthy volunteers, although the interindividual variability in absorption parameters was greater in the patient group. Variability in the extent of absorption would lead to differences in steady-state hydroxychloroquine concentrations between patients, potentially contributing to the variability in response observed in clinical practice.

Adult↗
PubMed1994

Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin.

1. The disposition of warfarin enantiomers and metabolites has been studied in 36 patients receiving chronic rac-warfarin therapy, titrated to approximately the same anticoagulant response. 2. A stereoselective h.p.l.c. assay was employed to determine the concentrations of (R)- and (S)-warfarin, (R,S)-warfarin alcohol and (S)-7-hydroxywarfarin in plasma and 24 h urine samples. The concentrations of (R)-7-hydroxywarfarin, (S,S)-warfarin alcohol and (R)-6- and (S)-6-hydroxywarfarin were also determined in urine samples. The fractions unbound of warfarin enantiomers were determined using equilibrium dialysis. 3. Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5-12 mg), in plasma concentrations of (S)-warfarin (0.48 mg l(-1); 0.11-1.02 mg l(-1)), (R)-warfarin (0.87 mg l(-1); 0.29-1.82 mg l(-1)), (R,S)-warfarin alcohol (0.31 mg l(-1); 0.02-0.72 mg l(-1)) and (S)-7-hydroxywarfarin (0.25 mg l(-1); 0.07-0.37 mg l(-1)) and the percentage unbound of (S)-warfarin (0.53%; 0.29%-0.82%) and (R)-warfarin (0.54%; 0.26%-0.96%). 4. The mean plasma clearances of warfarin enantiomers were 7.5 1 day-1 per 70 kg (2.5-22.1) for (S)-warfarin and 3.6 1 day-1 per 70 kg (1.6-8.8) for (R)-warfarin. There was a significant correlation between the estimated formation clearance of (S)-7-hydroxywarfarin and the clearance of (S)-warfarin, which accounted for much of the variability in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Warfarin metabolites: stereochemical aspects of protein binding and displacement by phenylbutazone.

The in vitro human serum albumin binding characteristics of the enantiomers of the major metabolites of warfarin [6-hydroxywarfarin (6-HW), 7-hydroxywarfarin (7-HW), (S)-warfarin alcohols [(S,S)- and (S,R)-WA], and (R,S)-warfarin alcohol [(R,S)-WA]] have been studied, using a stereospecific HPLC assay. Warfarin metabolites are less bound both within plasma and a 40 g/liter solution of human serum albumin than the enantiomers of warfarin. The reduced warfarin metabolites have a lower fraction unbound [1.33% for (S,R)-WA, 2.09% for (S,S)-WA, and 1.04% for (R,S)-WA] than hydroxylated metabolites [3.24% for (R)-6-HW, 4.26% (S)-6-HW, 4.49% for (R)-7-HW and 4.27% for (S)-7-HW] to HSA. Phenylbutazone produced a concentration-dependent increase in the unbound fraction of all metabolites. It was possible to predict the unbound fraction of warfarin metabolites based on the unbound fraction of warfarin enantiomers.

Humans↗
PubMed1993

Plasma protein binding of the enantiomers of hydroxychloroquine and metabolites.

The in vitro binding of the enantiomers of hydroxychloroquine and its three major metabolites in pooled plasma obtained from four healthy volunteers and the binding of the enantiomers of hydroxychloroquine to purified plasma proteins has been investigated. The plasma protein binding of hydroxychloroquine was found to be stereoselective. The (S)-enantiomer of hydroxychloroquine was 64% bound in plasma, while (R)-hydroxychloroquine was 37% bound. Fifty% of (S)-hydroxychloroquine was bound to a 40 g.l-1 solution of human serum albumin, while only 29% of the (R)-enantiomer was bound. The enantioselectivity of hydroxychloroquine binding was reversed in a 0.7 g.l-1 solution of alpha 1-acid glycoprotein with (R)-hydroxychloroquine being bound to a greater extent than its optical antipode (41% versus 29%). The enantiomers of the metabolites of hydroxychloroquine were bound to a similar extent to plasma and purified plasma proteins. Binding of hydroxychloroquine to plasma and purified proteins was found to be linear over the racemic concentration range of 50 to 1000 ng.ml-1 and hydroxychloroquine metabolite binding to plasma was linear over the range 25 to 500 ng.ml-1.

Blood Proteins↗
PubMed1993

Disposition of the enantiomers of hydroxychloroquine in patients with rheumatoid arthritis following multiple doses of the racemate.

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (+/- s.d.) renal clearance from blood of 41 +/- 11 ml min-1, approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.

Adult↗
PubMed1991

High-performance liquid chromatographic separation of the enantiomers of hydroxychloroquine and its major metabolites in biological fluids using an alpha 1-acid glycoprotein stationary phase.

An enantioselective two-stage off-line assay has been developed for the analysis of hydroxychloroquine and its three major metabolites in biological fluids. The first non-stereoselective stage of the assay (PRP-1 column) separates and quantitates parent drug and metabolites. Fractions containing hydroxychloroquine and each of the metabolites are collected manually, evaporated, reconstituted in mobile phase and re-injected onto an alpha 1-acid glycoprotein column to separate and determine proportions of individual enantiomers. Preliminary results from patients samples indicate that the disposition of hydroxychloroquine and its major metabolites is enantioselective. p6

Body Fluids↗