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K A Bachmann

Publications and source records attributed to K A Bachmann.

At least 37 records · Page 2Linked to original sources
PubMed1990

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.

Antipyrine↗
PubMed1989

Accuracy of two equations in determining normalized phenytoin concentrations.

The accuracy of two equations in normalizing total phenytoin concentrations in the presence of renal failure or hypoalbuminemia was evaluated in 11 renal failure and 23 hypoalbuminemic patients. Blood samples were obtained from hospitalized patients receiving phenytoin and were assayed for free and total phenytoin concentrations. Estimated normalized phenytoin concentrations based on free drug concentration were compared statistically with normalized concentrations calculated from the two equations via Student's t-test. The equation for normalizing phenytoin concentrations in hypoalbuminemic patients significantly underpredicted normalized phenytoin concentrations 15.7 +/- 8.5 versus 19.9 +/- 12.1 mg/L (p less than 0.001). In patients with renal failure, the mean phenytoin concentration from the respective equations and that based on free concentration were 14.1 +/- 6.2 and 14.0 +/- 7.9 mg/L, respectively. However, in 5 of 11 renal failure patients the equation resulted in over- or underprediction by at least 25 percent. Neither equation should be used clinically to normalize phenytoin concentrations in these patient populations.

Adult↗
PubMed1989

The suitability of carbamazepine as a single-sample probe of human mixed function oxidase activity.

1. Carbamazepine concentrations measured in plasma and plasma ultrafiltrates by fluorescence polarization immunoassay (f.p.i.a.) from 0 to 48 h post-dose were used to calculate CL, V, clearance of plasma unbound drug (CLunb), Vunb; mean (+/- SD) values for these were: 0.017 l/kg/h (+/- 0.004), 1.05 l/kg (+/- 0.14), 0.058 l/h/kg (+/- 0.012), and 4.28 l/kg (+/- 0.41), respectively. 2. A single-dose, single-sample procedure for estimating carbamazepine oral clearance was evaluated with a view to using carbamazepine as a probe in screening for host factor influences on human drug metabolism. Single sample estimates of carbamazepine clearance (CL) were closest to multiple sample values for carbamazepine clearance (CL) when blood samples were collected 48 h after carbamazepine ingestion. This was the case for plasma total carbamazepine and plasma unbound carbamazepine. 3. A value of 1.1 l/kg was used for V in calculating all single sample estimates of clearance (CL), and a value of 4.3 l/kg was used to calculate single sample estimates of clearance of plasma unbound drug (CLunb). The mean prediction error (MPE) was negatively biased for CL and CLunb values calculated from single carbamazepine concentrations in samples collected at 24, 36, and 48 h post-dose. MPE was less than 5% errant for CL and less than 1% errant for CLunb when those parameters were calculated from 48 h concentrations of plasma total carbamazepine or plasma unbound carbamazepine, respectively. Root mean squared error (r.m.s.e.) was lost lowest when 48 h post-dose samples were used for single-sample clearance estimates.

Administration, Oral↗
PubMed1989

The use of single-sample clearance estimates to probe hepatic drug metabolism in rats. IV. A model for possible application to phenotyping xenobiotic influences on human drug metabolism.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multi-sample estimates of clearance for carbamazepine, quinidine, and paracetamol. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates (CL) corresponded closely to multi-sample clearance estimates. Best post-dose sampling times were: carbamazepine, 3 h; quinidine, 10 h; and paracetamol, 6 h. 2. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of hepatic drug-metabolizing activity in rats. Valproic acid was investigated as a probe of microsomal and peroxisomal oxidases; antipyrine, theophylline, ethosuximide, carbamazepine and quinidine as probes of hepatic mixed-function oxidases (MFO), and paracetamol as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely, probe CL after xenobiotic pretreatment divided by control probe CL) was calculated for each probe. Eight pretreatments were used: phenobarbital (PB), beta-naphthoflavone (beta NF), polychlorinated biphenyls (PCB), rifampin, pregnenolone-16 alpha-carbonitrile (PCN), clofibric acid, cimetidine, and piperonyl butoxide. The effect of each xenobiotic pretreatment on all probe CL values was consolidated and plotted as the logarithm of the CI, and a distinct pattern or handprint evolved for each pretreatment. 4. We conclude that the use of multiple single-sample probes of hepatic MFO activity can be useful in structuring handprints to characterize xenobiotic-mediated effects on hepatic MFO. This minimally invasive in vivo approach may have application in investigating and possibly phenotyping MFO activity in human subpopulations that are subject to sustained exposure to particular xenobiotics.

Animals↗
PubMed1989

Optimal dosing of phenytoin: an evaluation of the timing and appropriateness of serum level monitoring.

The appropriateness of all serum phenytoin concentrations measured at this 294-bed, tertiary care institution over a 7-week period were evaluated. Each serum level was determined to be justified or unjustified based on either pharmacokinetic or clinical criteria. A total of 234 serum levels were measured in 58 patients. Thirty-eight (16%) of the levels were justified on a pharmacokinetic basis, whereas 70 (30%) were justified for clinical assessment of the patient. One hundred thirty (56%) of the serum levels could not be justified on any grounds. Also identified were distinct clinical situations for 13 patients for which monitoring of serum levels was warranted but not performed. Most phenytoin serum level measurements at this institution were not reasonably justified and may have been unnecessary. A yearly reduction in laboratory costs in excess of $9,000 was predicted if such serum levels had been ordered only when clearly indicated.

Adolescent↗
PubMed1988

Predicting the ciprofloxacin-theophylline interaction from single plasma theophylline measurements.

The effect of ciprofloxacin treatment on theophylline clearance was evaluated with a theophylline multiple dose, multiple sample protocol and with a single dose, single sample protocol. The object was to determine whether a single dose, single sample protocol for estimating theophylline clearance could be used as a screening strategy for evaluating host factor influences on theophylline clearance. Ciprofloxacin (750 mg per os) was administered every 12 h for nine doses in the multidose study and every 12 h for seven doses in the single dose protocol. Subjects were sixteen healthy, non-smoking young adult males. The oral clearance of theophylline at steady state, (CL/F)ss, decreased from a mean (+/- s.d.) value of 0.035 (+/- 0.008) 1 h-1 kg-1 to 0.024 (+/- 0.004) 1 h-1 kg-1 during ciprofloxacin treatment. Single sample estimates of theophylline clearance, CL/F, similarly decreased from 0.040 (+/- 0.014) 1 h-1 kg-1 to 0.018 (+/- 0.008) 1 h-1 kg-1. Mean theophylline clearances were significantly different when comparing control with ciprofloxacin treatment means (P less than 0.01), but were not different when comparing single sample vs multiple sample clearances for a given treatment (i.e. control or ciprofloxacin). It is concluded that a single dose, single sample strategy may be used in screening for host-factor influences on theophylline clearance.

Administration, Oral↗
PubMed1988

Multiple-dose pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to infected, seriously ill, elderly patients.

The pharmacokinetics of cefoperazone and sulbactam in combination were evaluated in six, elderly, seriously ill patients treated with the drug combination for intra-abdominal infections. After giving informed consent, three males and three females aged 63.5 to 77.5 (mean 67.9) years and weighing 54.5 to 86.8 (mean, 67.6) kg were treated with cefoperazone (2.0 g) and sulbactam (1.0 g) infused intravenously every 12 h for at least 5 days. Cefoperazone and sulbactam pharmacokinetics were characterized on both days 1 and 5 of treatment. Eleven serial blood samples were obtained just prior to and following dose 1 on days 1 and 5 of treatment. Mean estimates of cefoperazone maximal concentration in plasma (Cmax), area under the curve of drug concentration in plasma versus time (AUC), half-life (t 1/2), apparent volume of distribution by the area method (Varea), apparent volume of distribution at steady state (Vss), and total body clearance (CL) for day 1 (day 5) were 297.5 237.5) micrograms/ml, 1,247 (1,063) micrograms.h/ml, 7.0 (4.9) h, 16.1 (13.4) liter, 13.1 (14.4) liter, and 28.9 (34.2) ml/min, respectively. Day 1 (day 5) mean values for sulbactam Cmax, AUC, t 1/2, Varea, Vss, and CL were 110.3 (78.0) micrograms/ml, 228 (217) micrograms.h/ml, 3.4 (2.5) h, 26.1 (18.5) liter, 18.9 (15.4) liter, and 97 (94) ml/min, respectively. Both drugs evidenced slower elimination and greater pharmacokinetic variability in these patients compared with values previously reported for normal volunteers. As patients improved during the course of therapy, the only pharmacokinetic parameter significantly changed between days 1 and 5 was a shortened sulbactam t 1/2. Our inability to find substantial evidence of pharmacokinetic normalization may have been related to sample size and study duration. Both drugs were present in potentially therapeutic concentrations for the entire 12-h dosing interval, but without undue accumulation from days 1 to 5.

Abdomen↗
PubMed1988

The use of single sample clearance estimates to probe hepatic drug metabolism in rats. I.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multisample estimates of clearance. When plasma concentrations were measured at various post-dose times, both individual and mean values of single sample clearance estimates, Cl, corresponded closely to multisample clearance estimates, Cl, and significant differences between Cl and Cl could not be detected. 2. Best post-dose sampling times were: theophylline, 6 h; phenytoin, 2 h; valproic acid, 20 min; antipyrine, 4 h; and S-warfarin, 48 h. 3. When theophylline clearance was evaluated by both multisample and single sample experiments during diethyl ether versus urethane anaesthesia, clearances were about 50% slower for ether-anaesthetized rats. This outcome was qualitatively and quantitatively the same regardless of whether single sample or multiple sample clearances were estimated, and single sample theophylline clearances were virtually identical to multisample clearances under both anaesthetic conditions. 4. We conclude that multiple drugs can be potentially useful for probing hepatic drug metabolizing activity in rats when using a single plasma measurement to estimate clearance. An appropriate array of such probes might effectively be used to handprint host-factor influences on drug metabolizing activity.

Animals↗
PubMed1988

The use of single sample clearance estimates to probe hepatic drug metabolism in rats. II.

1. Single sample clearance estimates, Cl, were calculated for each of five drugs employed as probes of hepatic drug-metabolizing activity in rats. Probe drugs were theophylline, phenytoin, valproic acid, antipyrine, and S-warfarin. Cl values were calculated for each probe in animals pretreated with phenobarbital, isosafrole, beta-naphthoflavone, or clofibrate. Control animals were pretreated with vehicle only. 2. A clearance index (c.i., probe Cl after pretreatment divided by probe Cl control) was calculated for each probe and each pretreatment regimen, and data were consolidated to give different probe-based handprints of the pretreatment effects. 3. S-Warfarin was the least specific probe as its c.i. was greater than 1.0 subsequent to each pretreatment. Theophylline appeared to be the most selective probe since its c.i. deviated significantly from unity (3.56) only after beta-naphthoflavone pretreatment. Phenytoin exhibited c.i. values less than unity after each pretreatment indicating that it may not, when used as a single sample probe of hepatic drug-metabolizing activity, effectively discriminate between inductive or inhibitory effects of xenobiotics. 4. Multi-probe-based handprints of hepatic drug-metabolizing activity structured from simple single sample estimates of probe clearance have potential in the rapid screening of xenobiotic-induced alterations of drug-metabolizing enzyme activity.

Animals↗
PubMed1987

Use of three probes to assess the influence of sex on hepatic drug metabolism.

Clearances of phenytoin (PHT), ethosuximide, and theophylline were estimated by a single-dose, single-sample strategy in healthy, young adult men and women. PHT concentrations were measured in salivary ultrafiltrates, ethosuximide concentrations were measured in saliva, and theophylline concentrations were measured in plasma. Estimates of the clearances of these three probes of hepatic drug-metabolizing enzymes revealed a trend toward slightly lower clearances among women compared to men: mean PHT clearance 15% lower, ethosuximide clearance 27% lower, and theophylline clearance 14% lower. However, only differences in ethosuximide clearances were statistically significant. The use of oral contraceptive steroid (OCS) drugs on PHT and ethosuximide clearance was examined, and no significant effects were detected.

Adult↗
PubMed1986

Inability of ibuprofen to alter single dose phenytoin disposition.

The effect of ibuprofen treatment (1600 mg day-1 per os for 7 days) on single dose (300 mg per os) dispositional parameters of phenytoin (DPH) was evaluated in 10 healthy males. Ibuprofen slightly increased the free fraction of DPH from mean (+/- s.d.) value of 6.9 (+/- 0.7)% to 7.8 (+/- 0.3)% (P less than 0.01). DPH total clearance (CL/F) was not significantly changed going from a value of 0.027 (+/- 0.009) 1 h-1 kg-1 to 0.032 (+/- 0.014) 1 h-1 kg-1 (0.05 less than P less than 0.1). Intrinsic unbound DPH clearance (CLuint/F) was unaffected by ibuprofen treatment. Neither DPH's apparent volume of distribution (V/F) nor the apparent volume of distribution of unbound DPH (Vunb/F) were significantly altered by ibuprofen treatment. The slight changes in DPH plasma protein binding that are due to concurrent ibuprofen treatment in doses of 1600 mg day-1 are not likely to produce important changes in DPH dispositional parameters.

Adult↗
PubMed1983

Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats.

A dose-response curve for the hypoprothrombinemic effect of brodifacoum 3-[-3(4'-bromobiphenyl-4-yl) 1,2,3,4-tetrahydronaphth-1-yl] -4-hydroxycoumarin, was constructed using doses ranging from 0.1 to 0.33 mg/kg. Brodifacoum exhibited a remarkably steep dose-response curve. Brodifacoum failed to exhibit a dose-dependent effect on the degradation rate constant (kdeg) for prothrombin complex activity (PCA) after a PCA-synthesis-blocking dose of warfarin. Both phenobarbital pretreatment and SKF525A treatment altered to anticoagulant response to brodifacoum. Phenobarbital decreased the anticoagulant effect, whereas SKF525A increased it, suggesting that a substantial portion of brodifacoum-induced hypoprothrombinemia is mediated by brodifacoum itself rather than by metabolites. Finally, rats dosed orally with brodifacoum (0.2 mg/kg p.o.) were sacrificed in groups of 3-5 at various times up to 120 h after the dose. Brodifacoum was assayed in serum, small intestine, and liver by an HPLC method. Brodifacoum disappeared slowly from serum with a half-life of 156 h. Disappearance from small intestine was rapid, for 24 h, but intestinal levels began increasing from 24 to 72 h after the dose. Concentrations in liver were rapidly established, and exceeded serum concentrations by 20-fold. Brodifacoum levels in liver remained relatively constant for 96 h. Sustained liver concentrations after a single dose may partially account for brodifacoum's apparent potency relative to warfarin.

4-Hydroxycoumarins↗
PubMed1981

Convenient synthesis of 6-nor-9,10-dihydrolysergic acid methyl ester.

6-Nor-9,10-dihydrolysergic acid methyl ester (IV) was prepared by demethylation of 9,10-dihydrolysergic acid methyl ester (II) with 2,2,2-trichloroethyl chloroformate, followed by reduction of the intermediate carbamate (III) with zinc in acetic acid. The 6-ethyl-V and 6-n-propyl-VI derivatives were prepared by alkylation of IV with the appropriate halide. All of the ergoline derivatives were evaluated for stereotyped behavior in rats, with 6-nor-6-ethyl-9,10-dihydrolysergic acid methyl ester (V) being active but much less potent than apomorphine. Compound VI was evaluated for its effect on blood pressure; at a dose of 30 mg/kg ip, it significantly lowered, diastolic pressure in normotensive rats.

Animals↗
PubMed1976

Effect of phenylbutazone on the metabolic disposition of warfarin in the dog.

Phenylbutazone has been shown to modify the physiologic disposition of warfarin in the dog. Dogs pretreated with phenylbutazone for a week, and permitted to remain drug-free for an additional week, eliminated warfarin from plasma 2-3 times faster than non-pretreated controls with an average half-life of 7.8 hours. In-vitro hepatic microsomal metabolism of warfarin and cytochrome P-450 content were greater for hepatic microsomes derived from phenylbutazone pretreated animals.

Animals↗
PubMed1975

Phenylbutazone-warfarin interaction in the dog.

The administration of phenylbutazone together with warfarin to dogs resulted in an elevation of the free fraction of warfarin in the plasma from 2-6 to 8-0% thus providing direct support for the notion that phenylbutazone induced inhibition of warfarin binding to plasma proteins. This inhibition as evaluated by a kinetic method was accompanied by a two-fold decrease in the plasma half-life of warfarin from 18-4 h in control animals to 9-6 h in phenylbutazone-treated animals. Marked increases in warfarin-induced hypoprothrombinaemia were observed when at doses up to 8 mg kg-1 (orally) it was given with phenylbutazone (50 mg kg-1, orally). The unbound fraction of warfarin in canine plasma ranged from 1-7 to 4-3% indicating individual differences in the extent of the plasma binding of warfarin in the dog.

Animals↗
PubMed1975

Topical application of a chlordane-containing ectoparasiticide: effect on the plasma half-life of warfarin in dogs.

Brief exposure of dogs to topical chlordane solutions resulted in a significant and long-lasting decrease in the biological half-life of orally administered warfarin. The effect is presumed to be an expression of chlordane's well-documented inductive effect on hepatic microsomal drug metabolizing enzymes and its long-term storage in fat depots. The facility with which chlordane is absorbed through the intact skin of dogs may render casually-treated animals unsuitable for subsequent pharmacologic study for long periods of time.

Administration, Oral↗