Biomedical subjects
F Bochner
Publications and source records attributed to F Bochner.
Effects of omeprazole and cimetidine on the urinary metabolic ratio of proguanil in healthy volunteers.
OBJECTIVE: To examine the effects of omeprazole and cimetidine on the urinary recovery and metabolic ratio of proguanil in healthy subjects. METHODS: A metabolic interaction study was conducted in 12 young, healthy extensive metabolisers of proguanil, a CYP2C19 substrate, following a single 100 mg oral dose by analysis of urine collected for 8 hours. RESULTS: Concomitant administration of omeprazole (20 mg), a CYP2C19 substrate, had no significant effect on the urinary recovery of proguanil or cycloguanil, or the ratio of cycloguanil to proguanil [mean 0.76 (95% CI: 0.53 to 0.98) proguanil alone; mean 0.65 (95% CI: 0.40 to 0.89) proguanil plus omeprazole]. In contrast, cimetidine (400 mg), a general CYP inhibitor and renal organic cation secretion inhibitor, decreased the urinary recovery of cycloguanil and reduced the metabolic ratio from a mean of 0.76 to 0.54 (P < 0.01). In 3 poor metabolisers of proguanil, cimetidine had no effect on the proguanil metabolic ratio. CONCLUSION: The concomitant administration of omeprazole or cimetidine will not result in phenocopying extensive metabolisers of proguanil, although cimetidine inhibits the formation of cycloguanil in extensive metabolisers.
The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans.
OBJECTIVES: We studied the disposition of dextromethorphan in extensive and poor metabolizer subjects, as well as the effect of this polymorphism on the antitussive action of dextromethorphan. METHODS: Six extensive metabolizers were studied on four occasions: (1) after 30 mg dextromethorphan, (2) after 30 mg dextromethorphan 1 hour before 50 mg quinidine, (3) after placebo, and (4) after 50 mg quinidine. Six poor metabolizers were studied on two occasions: (1) after 30 mg dextromethorphan and (2) after placebo. Blood and urine were collected over 168 hours and assayed for dextromethorphan, total (conjugated and unconjugated) dextrorphan, 3-methoxymorphinan, and total 3-hydroxymorphinan. On each occasion at each blood sampling time, capsaicin was administered as an aerosol to provoke cough. RESULTS: Dextromethorphan area under the plasma concentration-time curve (AUC) was 150-fold greater in the poor metabolizers than in the extensive metabolizers, and quinidine increased the AUC in extensive metabolizers 43-fold. The median dextromethorphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in extensive metabolizers given quinidine, and 2.4 hours in extensive metabolizers. For dextrorphan (as total), the AUC was reduced 8.6-fold in poor metabolizers; quinidine had no effect on the AUC. The median half-life was 10.1 hours in poor metabolizers, 6.6 hours in extensive metabolizers given quinidine, and 1.4 hours in extensive metabolizers. The apparent partial clearance of dextromethorphan to dextrorphan was 1.2 L/hr in poor metabolizers, 78.5 L/hr in extensive metabolizers given quinidine, and 970 L/hr in extensive metabolizers. There was a strong (r2 = 0.82) and significant (p < 0.01) positive correlation between the prestudy urinary metabolic ratios and the partial clearances of dextromethorphan to dextrorphan. There was very large intersubject variability in responsiveness to capsaicin. There was no difference in the capsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model. CONCLUSION: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.
Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism.
1. Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been linked to the CYP2C19-mediated genetic polymorphism in S-mephenytoin oxidative metabolism. In many countries, rac-mephenytoin can no longer be administered to humans and hence proguanil may be a more suitable probe for phenotyping purposes. 2. There are limited data on the pharmacokinetics of PG and CG and in particular, whether there is a relationship between the urinary metabolic ratio of PG and its partial intrinsic clearance to CG. 3. The disposition of a 100 mg oral dose of PG was investigated in 10 subjects with widely varying metabolic ratios (pre-study urinary metabolic ratio CG to PG = 0.068 to 1.11). Blood samples and all urine were collected for 96 h and assayed for PG and CG by h.p.l.c. 4. The urinary recovery of PG ranged from 30 to 69% of the dose and for CG from 2.8 to 32% of the dose. The overall urinary recovery of PG plus CG ranged from 54 to 77% of the dose. The AUC for PG ranged from 3.2 to 9.5 mg l-1 h whereas for CG it was from 0.02 to 0.71 mg l-1 h. The partial intrinsic clearance to CG ranged 25-fold from 0.41 to 10.1 l h-1. 5. There was a highly significant (r2 = 0.96, P < 0.001) relationship between the urinary metabolic ratio for PG (as CG/PG) and its partial intrinsic clearance to CG. 6. These data have provided evidence for the justification of the use of the urinary metabolic ratio of proguanil for population phenotyping purposes, provided systematic variation in renal drug clearance between populations is considered.
Evaluation of the intestinal absorption of erythromycin in man: absolute bioavailability and comparison with enteric coated erythromycin.
To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Pharmacokinetic considerations in gastrointestinal motor disorders.
Although it has been recognised that alterations in gastrointestinal motility, whether induced by physiological or pathological processes, have significant effects on the pharmacokinetics of orally administered drugs, this subject has received inappropriately little attention. Studies relating to this topic have focused on healthy volunteers and animals and have largely been confined to the effects of single drug doses. There is limited information about the effects of disease on pharmacokinetics under steady-state conditions. Changes in gastrointestinal motility may affect the pharmacokinetics of orally administered drugs by altering the rate of delivery, bioavailability or mucosal absorption of the drug. In general the rate of absorption and time taken to achieve maximal plasma concentrations for well absorbed drugs may be modified by changes in gastrointestinal motility, but overall bioavailability is not usually affected. In these cases the therapeutic and clinical effects of the alteration in pharmacokinetics will, therefore, depend on which parameters are important for the action of the drug. For poorly absorbed drugs both the rate of absorption and bioavailability are likely to be altered by changes in gastrointestinal motility. However, the complex effects of food and disease, as well as the properties and formulation of any drug (solubility, ease of dispersion, delayed release formulation) often make the prediction of the magnitude, or even the direction, of any effect difficult to predict. Drugs with direct effects on gastrointestinal motility may influence their own patterns of absorption. In patients with gastrointestinal motility disorders, drugs administered in a controlled release formulation, or those with poor bioavailability, are most likely to have a poorly predictable therapeutic effect. Care should be taken to ensure that the formulation of the drug, its timing of administration in relation to meals and the use of coadministered drugs optimise, or at least ensure consistent absorption.
Aspirin for myocardial infarction. Clinical pharmacokinetic considerations.
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How can hospitals ration drugs? Drug rationing in a teaching hospital: a method to assign priorities. Drug Committee of the Royal Adelaide Hospital.
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The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.
1. The enzyme kinetics of dextromethorphan O-demethylation in liver microsomes from three extensive metabolisers (EM) with respect to CYP2D6 indicated high (Km1 2.2-9.4 microM) and low (Km2 55.5-307.3 microM) affinity sites whereas microsomes from two poor metabolisers (PM) indicated a single site (Km 560 and 157 microM). Similar differences were shown for 3-methoxymorphinan O-demethylation to 3-hydroxymorphinan (Km 6.9-9.6 microM in EM subjects; Km 307 and 213 microM in PM subjects). 2. Dextromethorphan O-demethylation was inhibited competitively by quinidine (Ki 0.1 microM), rac-perhexiline (Ki 0.4 microM), dextropropoxyphene (Ki 6 microM), rac-methadone (Ki 8 microM), and 3-methoxymorphinan (Ki 15 microM). These compounds were also potent inhibitors of 3-methoxymorphinan O-demethylation with IC50 values ranging from 0.02-12 microM. Anti-LKM1 serum inhibited both dextromethorphan and 3-methoxymorphinan O-demethylations in a titre-dependent manner. 3. The Michaelis-Menten constant for dextromethorphan N-demethylation to 3-methoxymorphinan (Km 632-977 microM) and dextrorphan N-demethylation to 3-hydroxymorphinan (Km 1571-4286 microM) did not differ between EM and PM microsomes. These N-demethylation reactions were not inhibited by quinidine and rac-methadone or LKM1 antibodies. 4. Dextromethorphan and 3-methoxymorphinan are metabolised by the same P450 isoform, CYP2D6, whereas the N-demethylation reactions are not carried out by CYP2D6.
Therapeutic drug monitoring and patient outcome. A review of the issues.
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Dextromethorphan metabolism in rat: interstrain differences and the fate of individually administered oxidative metabolites.
1. Dextromethorphan undergoes O- and N-demethylation, with the resultant metabolites being further N- and O-demethylated respectively to 3-hydroxymorphinan. The polymorphically expressed O-demethylation reaction is catalysed by P4502D1 in the Sprague-Dawley (SD) rat. The Dark-Agouti (DA) rat lacks this enzyme. 2. The aims were: (1) to determine if there were strain differences also in the Hooded Wistar (HW) and Albino Wistar (AW) rats with respect to the four demethylation reactions after dextromethorphan 20 mg/kg intraperitoneally; (2) to investigate the inhibition of the demethylation reactions by quinine and quinidine (each 40 mg/kg i.p.) in the above strains; and (3) to investigate the fate of separately administered metabolites (5 mg/kg i.p.) of dextromethorphan in the SD strain. 3. The total recovery of dextromethorphan and metabolites in the four strains ranged from 38 to 64% of the dose. The O-demethylation ratios (expressed as the ratio of urinary total dextrorphan divided by dextromethorphan) in the AW and DA strains were similar but less than in the SD/HW strains; the N-demethylation ratios (expressed as the ratio of urinary total 3-hydroxymorphinan plus 3-methoxymorphinan divided by dextromethorphan) in the DA and SD strains were similar but greater than in the AW and HW strains. Quinine and quinidine significantly reduced the O-demethylation ratio in the SD and DA rat strains, and the N-demethylation ratio in the SD strain. 4. In the SD rat the major metabolic route was via O-demethylation to dextrorphan. The source of 3-hydroxymorphinan is primarily from N-demethylation of dextromethorphan to 3-methoxymorphinan and its subsequent O-demethylation to 3-hydroxymorphinan. The O-demethylation metabolic ratio for dextromethorphan should be calculated as the quotient of urinary total dextrorphan divided by dextromethorphan.
The influence of pharmacogenetics on opioid analgesia: studies with codeine and oxycodone in the Sprague-Dawley/Dark Agouti rat model.
In the Sprague-Dawley (SD) rat, the O-demethylation of codeine to morphine is catalyzed by cytochrome P4502D1 (CYP2D1), which is absent in the female Dark Agouti (DA) rat. Oxycodone is similar in structure to codeine but, in contrast, has an analgesic potency in humans similar to morphine. The aim of the study was to test whether the DA rat and the SD rat pretreated with the CYP2D1 inhibitor quinine showed attenuation in analgesia to codeine and oxycodone. With the use of the tail flick model, dose-response curves were constructed to codeine, morphine, oxycodone and oxymorphone (the O-demethylated metabolite of oxycodone) in both rat strains. Codeine did not induce analgesia in the DA rat and there was a 60% reduction in codeine analgesia in the SD rat pretreated with quinine in comparison to the untreated SD rat. In the DA rat, the ED50 to oxycodone was increased 10-fold but there was a significant (P = .0001) prolongation in the duration of analgesia in comparison to that in the untreated SD rat. In the quinine-pretreated SD rat, there was no reduction in oxycodone analgesia but the duration of analgesia was also prolonged. It was concluded that 1) codeine-mediated analgesia requires the formation of morphine through the functional activity of CYP2D1 and 2) oxycodone-mediated analgesia may only be partly dependent on CYP2D1.
Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism.
Codeine and morphine are endogenous substances. Following administration of exogenous codeine the biotransformation to morphine is catalyzed by CYP2D6, which exhibits a genetic so-called debrisoquine/sparteine polymorphism which is expressed in two phenotypes, the extensive and poor metaboliser phenotypes. Poor metabolisers form only trace amounts of morphine. If endogenous morphine is biosynthesised in humans via similar routes as in the poppy plant, two of the steps involved are mediated by CYP2D6, namely thebaine O-demethylation to oripavine and codeine O-demethylation to morphine. Poor metabolisers should therefore have a much lower endogenous morphine formation than extensive metabolisers. The urinary excretion of endogenous codeine and morphine were investigated in 20 extensive and 20 poor metabolisers of CYP2D6. Substantial interindividual variation in codeine (7-6851 pmol/24 hr) and morphine (32-35471 pmol/24 hr) excretion was observed. However, there were no phenotype-related differences in endogenous codeine and morphine excretion. Administration of the competitive CYP2D6 inhibitor quinidine had no significant effect on endogenous codeine and morphine excretion in extensive metabolisers. In conclusion, in contrast to exogenous codeine O-demethylation to morphine CYP2D6 appears not to be involved in the biosynthesis of morphine in humans.
The clinician and therapeutic drug monitoring in the 1990s.
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Primary and secondary oxidative metabolism of dextromethorphan. In vitro studies with female Sprague-Dawley and Dark Agouti rat liver microsomes.
The O-demethylation of dextromethorphan (DM) to dextrorphan (DR) is catalysed by the polymorphic CYP2D6 (cytochrome P4502D6) isozyme in man. DM is commonly used as a probe for phenotyping subjects as either poor or extensive metabolizers for the debrisoquine/sparteine oxidative polymorphism via CYP2D6. The enzyme kinetics of DM O- and N-demethylation, and the N- and O-demethylations of the primary metabolites DR and 3-methoxymorphinan (3MM), respectively, were studied in liver microsomes from female Dark Agouti (DA) rats, the poor metabolizer counterpart, and female Sprague-Dawley (SD) rats, the extensive metabolizer counterpart. The formation of metabolites was quantified by HPLC with fluorescence detection and kinetic parameters were calculated. The intrinsic clearance (Vmax/Km) of the O-demethylation of 3MM to 3-hydroxymorphinan (3OHM) was 180-fold lower in DA rats (0.11 vs 20.77 mL/hr/mg) due to a 60-fold higher Km (108.7 vs 1.76 microM) and 3-fold lower Vmax (11.5 vs 35.95 nmol/mg/hr). The kinetics for DR N-demethylation to 3OHM did not differ between rat strains. The Michaelis-Menten constant (Km) for DM N-demethylation to 3MM was similar between SD and DA rats (85.04 vs 68.99 microM); however, SD rats displayed a 2-fold higher Vmax (83.37 vs 35.49 nmol/mg/hr) and intrinsic clearance (0.96 vs 0.51 mL/hr/mg). The O-demethylation of DM to DR in SD rats showed a high and low affinity enzyme component, with the high affinity intrinsic clearance contributing 98% of the total intrinsic clearance in these rats. DM O-demethylation in DA rats was characterized by a single enzyme system. The high affinity O-demethylating enzyme in SD rats showed a 20-fold lower Km (2.5 vs 55.6 microM) and a three-fold higher Vmax (51.04 vs 16.84 nmol/mg/hr) resulting in a 66-fold higher intrinsic clearance (20.04 vs 0.31 mL/hr/mg) compared to DA rats. Quinine, dextropropoxyphene, (+/-)methadone and (+/-)propafenone were shown to be potent inhibitors of 3MM and DM O-demethylation but did not inhibit DR or DM N-demethylation at similar concentrations. SD and DA rats showed a clear strain difference in 3MM O-demethylation and DM O-demethylation. In contrast, DR N-demethylation and DM N-demethylation do not appear to be under genetic control in the female SD-DA rat model. Kinetic parameters and inhibition studies suggest that 3MM and DM O-demethylation pathways in the rat may be mediated by the same cytochrome P450 isozyme.
The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.
1. Single oral doses of 100 mg racemic ketoprofen were given to 15 patients (age range: 51-79 years) with rheumatoid arthritis and a range of creatinine clearances (CLCR) from 26 to 159 ml min-1. 2. The fractions unbound of (R)- and (S)-ketoprofen in plasma were determined for each subject after in vitro addition of rac-ketoprofen (enantiomer range: 1.00-6.00 micrograms ml-1) to pre-dose plasma. 3. An index of the antiplatelet effect of ketoprofen in vitro was measured as inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood (pre-dose) spiked with rac-ketoprofen. 4. In vivo studies revealed significant associations (P < 0.05) between the reciprocal of AUC for both unbound and total (bound plus unbound) (S)-ketoprofen and CLCR. Corresponding relationships were also observed for the (R)-enantiomer of ketoprofen. In addition, the half-life of each enantiomer was negatively correlated with CLCR. There was a positive relationship between the 24 h urinary recovery of combined non-conjugated and conjugated (R)-ketoprofen and CLCR while that for the (S)-stereoisomer failed to reach statistical significance (P > 0.05). 5. There was no difference between AUC for (R)- and (S)-ketoprofen for either unbound or total drug. 6. The mean +/- s.d. percentage unbound of (S)-ketoprofen in plasma (0.801 +/- 0.194%) exceeded (P < 0.05) the corresponding value for its optical antipode (0.724 +/- 0.149%). The percentage unbound of the (S)-enantiomer was higher at 6.00 micrograms ml-1 than that at enantiomer concentrations of 3.50 micrograms ml-1 and below, where it was invariant. The percentage unbound of (R)-ketoprofen was independent of plasma concentration up to 6.00 micrograms ml-1. There were no correlations between the percentage unbound of each enantiomer and either serum albumin concentration or CLCR. 7. The relationship between the serum concentration of unbound (S)-ketoprofen and the percentage inhibition of platelet TXB2 generation was described by a sigmoidal Emax equation for each patient. There was no correlation between the unbound concentration of (S)-ketoprofen in serum required to inhibit platelet TXB2 generation by 50% (EC50) and CLCR. The mean +/- s.d. EC50 was 0.216 +/- 0.143 ng ml-1. 8. These data indicate that diminished renal function is associated with an increased exposure to unbound (S)-ketoprofen, presumably due to regeneration of parent aglycone arising from the hydrolysis of accumulated acyl-glucuronide conjugates. The apparent sensitivity of platelet cyclo-oxygenase to the inhibitory effect of (S)-ketoprofen was not influenced by renal function.
Plasma concentrations and renal clearance of morphine, morphine-3-glucuronide and morphine-6-glucuronide in cancer patients receiving morphine.
The plasma concentrations and renal clearance values of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were determined in 11 adult cancer patients maintained on a long term oral morphine dosage (10 to 100mg every 4h). Concentrations in plasma and urine were determined by a specific high performance liquid chromatography assay. In this group of patients, whose creatinine clearance values ranged from 52 to 180 ml/min (3.12 to 10.8 L/h), average steady-state plasma concentrations of morphine, M3G and M6G were related (p < 0.01) to the morphine dose per kilogram of bodyweight. The mean total urinary recovery as morphine, M3G and M6G was 74.6 +/- 26.5% of the dose. Renal clearance values for M3G and M6G were closely related (r2 = 0.80; p < 0.0005). It was not possible to detect a relationship between the renal clearance of morphine, M3G and M6G, and that of creatinine. The renal tubular handling of all 3 compounds showed wide interindividual variation, and there was evidence of either net renal tubular secretion or reabsorption. There was no apparent relationship between plasma morphine and M6G concentrations and pain relief.
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.