Theophylline Kinetics: Dose Dependency and Single Sample Prediction of Clearance

Bachmann, Kenneth; Schwartz, Jules I.; Forney, Robert B.; Jáuregui, Luis

doi:10.1159/000138062

Cited by 17 publications

(10 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have described the suitability of the ophylline as a single-sample probe of hepatic mixed function oxidase on the basis of its pharmacokinetics [12] and have demon strated the fidelity with which such single sample CL estimates can qualitatively and quantitatively predict the influence of host factors on theophylline CL when compared to more classical multisample-based CL esti mates [13]. In the present investigation, our objective was to evaluate the selectivity of theophylline metabolism in rats as a prelimi nary means of determining whether it is likely to be a useful selective in vivo single-sample probe of cytochrome P-450 activity in hu mans as well.…”

Section: Discussionmentioning

confidence: 99%

In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

Bachmann

Sanyal²,

Potter³

et al. 1993

Pharmacology

Self Cite

View full text Add to dashboard Cite

The role of various subfamilies of rat hepatic cytochrome P-450 in the oxidation of theophylline was evaluated by comparing theophylline clearance in control rats and those pretreated with relatively selective inducers and inhibitors of the cyto-chromes P-450. Pretreatment with the CYP1A inducer, β-naphthofiavone (BNF), increased theophylline clearance 4.5-fold (p < 0.001), and the CYP1A inhibitor, α-naphthoflavone, significantly attenuated the BNF effect. Pretreatment with phenobarbital, an inducer of CYP2B/C in rats, had a far more modest effect, increasing theophylline clearance only 1.6-fold (p < 0.005). The phenobarbital-mediated increase in theophylline clearance was attenuated by orphenadrine, a CYP2B/C inhibitor. The CYP2E inducer, isoniazid and the CYP2E inhibitor, diallyl sulfïde were virtually without effect, as was the CYP4A inducer, clofibrate, and the CYP4A inhibitor, 10-undecynoic acid. Ajmaline, and inhibitor of CYP2D, was also without any effect on theophylline clearance. While the powerful CYP3A inducer clotrimazole did not increase theophylline clearance, troleandomycin, an inhibitor of CYP3A, did slow theophylline clearance by about 25% (p < 0.002). Together, these findings suggest that CYP1A is principally responsible for the overall oxidation of theophylline in rats, and that CYP2B/C probably also mediates some theophylline oxidation. The involvement of CYP2D, CYP2E, CYP4A, and CYP3A is relatively trivial.

show abstract

Section: Discussionmentioning

confidence: 99%

In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

Bachmann

Sanyal²,

Potter³

et al. 1993

Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have previously described single dose, single-sample protocols for estimating clearances of theophylline [8], PHT [9], and ethosuximide [10]. The theory underly ing the development of single-dose, single sample estimates of antipyrine clearance was first described by Dossing et al [11].…”

mentioning

confidence: 99%

Use of Three Probes to Assess the Influence of Sex on Hepatic Drug Metabolism

et al. 1987

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…A predose blood sample was also col lected at this time. 5 ml of whole blood was drawn into a heparin-anticoagulated evacuated tube (VacuTainer) at each of the following times relative to the single PHT dose: immediately before (time zero) and 2,4,8,12,24,36, and 48 h after the dose. Saliva was also collected at these times.…”

Section: Protocolmentioning

confidence: 99%

“…We have extended those observa tions to show that antipyrine clearance can be estimated with a single salivary sample of antipyrine [7], We have recently described a protocol for using a single plasma sample of theophylline in predicting its clearance and shown how this method accurately predicts the quantitative impact of cimetidine coad ministration on theophylline clearance [8]. We now describe the conditions which per mit phenytoin (PHT) to be used as a probe of MFO activity and the prediction of its intrin sic clearance from the collection of a single salivary sample.…”

mentioning

confidence: 94%

Phenytoin as a Probe of Drug Metabolism

et al. 1985

Self Cite

View full text Add to dashboard Cite

Phenytoin (PHT) was administered in single 300-mg doses to each of 12 healthy, male subjects. Serial blood samples and salivary samples were collected for the next 48 h, and concentrations of plasma total PHT, unbound plasma PHT (plasma ultrafiltrates), and salivary PHT (salivary ultrafiltrates) were measured by immunofluorescence polarization. The following parameters were estimated: CL_int/F, CL’_int/F, V/F, and total and unbound PHT plasma disappearance half-lives. Estimates of CL’_int/F (CL’_int/F) were calculated from single 48-hour salivary PHT measurements. Mean (± SD) values were 0.026 ± 0.009 l·h^–1·kg^–1, 0.385 ± 0.148 l·h^–1 kg^–1 12.6 ± 3.5 l/kg (referenced to unbound drug), 28.0 ± 12.1 h, and 25.9 ± 13.5 h, respectively. When V/F referenced to unbound PHT was set at 14 1/kg, CL’_int/F estimates were good predictors of the actual CL’_int/F values demonstrating a mean prediction error of-0.012 l·h^–1·kg^–1. These data demonstrate that under specified conditions, intrinsic unbound PHT clearance can be estimated from a single PHT measurement in saliva, thereby permitting PHT to be used safely and sampled simply and noninvasively as a probe of hepatic mixed function oxygenase activity in humans.

show abstract

Theophylline Kinetics: Dose Dependency and Single Sample Prediction of Clearance

Cited by 17 publications

References 8 publications

In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

Use of Three Probes to Assess the Influence of Sex on Hepatic Drug Metabolism

Phenytoin as a Probe of Drug Metabolism

Contact Info

Product

Resources

About