Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure

Ritonavir, a potent inhibitor of cytochrome P450 isoform 3A (CYP3A) activity, is frequently used to boost the effects of protease inhibitors at doses of 100-400 mg per day; however, human data regarding the optimal dose required for boosting are limited. This study systematically evaluated the ritonavir dose-response relationship on presystemic and systemic CYP3A metabolism using the human immunodeficiency virus integrase inhibitor elvitegravir and midazolam as probe substrates. Ritonavir administered once daily with elvitegravir exhibited nonlinear pharmacokinetics, with a 119-fold increase in the area under the plasma concentration-time curve over the dosing interval over a 20- to 200-mg dose range. The 20-mg dose of ritonavir substantially reduced CYP3A-mediated clearance (CL), as evidenced by a 66% reduction in midazolam CL that plateaued to 17% of baseline activity at a 100-mg dose. Maximum inhibition of elvitegravir apparent oral CL was achieved with ritonavir doses of 50-100 mg. Elvitegravir and ritonavir were generally well tolerated in this study. These data provide a critical understanding of ritonavir's dose-response relationship for inhibition of CYP3A activity in humans.     

Effect of grapefruit juice on digoxin pharmacokinetics in humans.

OBJECTIVES: Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism. METHODS: Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDR1 genetic polymorphism in exon 26 (C3435T). RESULTS: Grapefruit juice had no significant effect on the maximum plasma drug concentration (C(max)) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P =.01) during grapefruit juice administration. The digoxin renal clearance remained unchanged during both periods. No relationship between MDR1 C3435T genotype and early digoxin pharmacokinetic changes could be detected. CONCLUSION: The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assessed by use of digoxin disposition kinetics.     

Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug

The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).     

Low-dose ritonavir moderately enhances nelfinavir exposure

BACKGROUND: The protease inhibitor ritonavir is increasingly administered at subtherapeutic doses in highly active antiretroviral treatment, to utilize its potential for drug interactions and to enhance the plasma concentrations of other concomitantly prescribed protease inhibitors. The addition of low doses of ritonavir to nelfinavir was investigated to describe the extent of pharmacokinetic interaction. METHODS: In this randomized, open-label, one-sequence crossover study, nelfinavir 1250 mg twice a day was dosed for 17 days, followed by 14 days of nelfinavir 1250 mg twice a day plus low doses of ritonavir of either 100 mg or 200 mg orally. Twenty-four healthy volunteers were evaluated for pharmacokinetics of nelfinavir, its metabolite M8, and ritonavir. Plasma concentrations were measured up to 12 hours after morning and evening dosing, respectively, on days 14 and 31. RESULTS: Ritonavir increased the area under the plasma concentration-time curve (AUC) of nelfinavir by 20% (P =.024) and 39% (P =.001) after morning and evening administration, respectively. The AUC of nelfinavir metabolite M8 was increased by 74% and 86% after morning and evening dosing (P <.001 for both). CONCLUSION: During ritonavir combination therapy a clear although minor drug effect on nelfinavir pharmacokinetics was demonstrated but no dose effect was shown.     

Digoxin disposition kinetics in dogs before and during azotemia

The purpose of this study was to evaluate the disposition kinetics of digoxin after the administration of a single intravenous dose to the same dogs before and during azotemia. The digoxin plasma concentration-time data were fitted to a multicompartment model using nonlinear regression analysis. During azotemia, the biological half-life of digoxin was prolonged in six of seven dogs, while digoxin renal clearance, body clearance and apparent volume of distribution were significantly decreased. There was a corresponding increase in the apparent volume of the "central" compartment of digoxin. Approximately 45% of a digoxin dose was excreted by the kidney in these animals indicating a substantial nonrenal component to digoxin elimination in the dog. This nonrenal elimination did not change during azotemia, despite a decrease in renal clearance by 61%.     

Alprazolam-ritonavir interaction: implications for product labeling

BACKGROUND: Pharmacokinetic interactions involving antiretroviral therapies may critically influence the efficacy and toxicity of these drugs, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor ritonavir is of particular concern since it both inhibits and induces the activity of cytochrome P450 3A (CYP3A) isoforms. METHODS: The inhibitory effect of ritonavir on the metabolism of alprazolam, a CYP3A-mediated reaction in humans, was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer subjects received 1.0 mg of alprazolam concurrent with low-dose ritonavir (four doses of 200 mg) or with placebo. RESULTS: Ritonavir was a potent in vitro inhibitor of alprazolam hydroxylation. The 50% inhibitory concentration was 0.11 micromol/L (0.08 microg/mL); this is below the usual therapeutic plasma concentration range (generally exceeding 2 microg/mL). In the clinical study, ritonavir reduced alprazolam clearance to 41% of control values (P < .001), prolonged elimination half-life (mean values, 30 versus 13 hours; P < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. CONCLUSION: Consistent with in vitro results, administration of low doses of ritonavir for a short duration of time resulted in large impairment of alprazolam clearance and enhancement of clinical effects. Removal from product labeling of a warning against coadministration of ritonavir and alprazolam was based on a previous study only of extended exposure to ritonavir, in which CYP3A induction offset inhibition. Kinetic interactions involving antiretroviral therapies may be complex and time dependent. Product labeling should reflect this complexity.     

Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir

Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A), and it is used accordingly for the pharmacoenhancement of other antiretrovirals. Paradoxically, ritonavir induces the clinical metabolism and clearance of many drugs. The mechanism by which ritonavir inhibits and induces clinical drug metabolism is unknown. Ritonavir induces CYP2B6 in human hepatocytes. This investigation tested the hypothesis that ritonavir induces human CYP2B6 in vivo. Thirteen healthy human immunodeficiency virus-negative volunteers underwent a three-way sequential crossover protocol, receiving racemic bupropion after nothing (control), 3 days of treatment with ritonavir, and 2.5 weeks of treatment with ritonavir (400 mg twice a day). Stereoselective bupropion hydroxylation was used as an in vivo probe for CYP2B6 activity. Plasma and urine (R)- and (S)-bupropion and (R,R)- and (S,S)-hydroxybupropion concentrations were measured by liquid chromatography-mass spectrometry. Racemic, (R)-, and (S)-bupropion plasma ratios of the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) (ritonavir/control) were significantly reduced to 0.84, 0.86, and 0.80, respectively, after 3 days of ritonavir treatment and to 0.67, 0.69, and 0.60 after steady-state ritonavir treatment. Apparent oral clearances for racemic, (R)-, and (S)-bupropion all were significantly increased by 1.2-fold after 3 days of ritonavir treatment and by 1.4-, 1.7-, and 1.5-fold after steady-state ritonavir treatment. The plasma (S,S)-hydroxybupropion/(S)-bupropion AUC(0-72) ratio was significantly increased by ritonavir. Formation clearances of both (R,R)- and (S,S)-hydroxybupropion were increased 1.8-fold after 3 days of ritonavir treatment and 2.1-fold after steady-state ritonavir treatment. These results show that ritonavir induces human CYP2B6 activity. Induction is rapid, occurring after only 3 days of ritonavir, and is sustained for at least 2 weeks. The ritonavir induction of CYP2B6 activity may have significant implications for drug interactions and clarify previously unexplained interactions.     

Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.

BACKGROUND: The antidiarrheal drug loperamide is frequently used to treat ritonavir-associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its low bioavailability and its poor penetration of the blood-brain barrier, both of which might be altered by ritonavir, a potent P-glycoprotein and cytochrome P4503A inhibitor. METHODS: A 16-mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo. Detailed pharmacokinetics of loperamide and its metabolites were determined over 72 hours. Central opioid effects were measured by evaluation of pupil diameter, cold pressor test, and transcutaneous PCO2 and PO2. RESULTS: Ritonavir caused a major pharmacokinetic interaction, increasing the area under the concentration-time curve of loperamide from 104 +/- 60 h x pmol/ml after placebo to 276 +/- 68 h. pmol/ml and delayed formation of the major metabolite desmethylloperamide (time to reach maximum concentration after drug administration [t(max)], 7.1 +/- 2.6 hours versus 19.6 +/- 9.1 hours). The urinary metabolic ratio of loperamide increased 3 times whereas the total molar amount of loperamide and metabolites excreted in urine remained unchanged. No central pharmacodynamic effects were observed after coadministration of loperamide with either ritonavir or placebo. CONCLUSION: This study demonstrates a major metabolic interaction probably by cytochrome P4503A4 with no evidence of P-glycoprotein involvement. This might explain the lack of central effects after ritonavir.     

Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design

We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.     

Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers

AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.     

Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein

OBJECTIVE: Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein. METHODS: Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively. RESULTS: Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration. CONCLUSION: We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.     

Pharmacokinetics and interactions of a novel antagonist of chemokine receptor 5 (CCR5) with ritonavir in rats and monkeys: role of CYP3A and P-glycoprotein

The mechanisms of pharmacokinetic interactions of a novel anti-human immunodeficiency virus (anti-HIV-1) antagonist of chemokine receptor 5 (CCR5) [2-(R)-[N-methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)amino]-3-methylbutanoic acid (MRK-1)] with ritonavir were evaluated in rats and monkeys. MRK-1 was a good substrate for the human (MDR1) and mouse (Mdr1a) multidrug resistance protein transporters and was metabolized by CYP3A isozymes in rat, monkey, and human liver microsomes. Both the in vitro MDR1-mediated transport and oxidative metabolism of MRK-1 were inhibited by ritonavir. Although the systemic pharmacokinetics of MRK-1 in rats and monkeys were linear, the oral bioavailability increased with an increase in dose from 2 to 10 mg/kg. The area under the plasma concentration-time curve (AUC) of MRK-1 was increased 4- to 6-fold when a 2 or 10 mg/kg dose was orally coadministered with 10 mg/kg ritonavir. Further pharmacokinetic studies in rats indicated that P-glycoprotein (P-gp) inhibition by ritonavir increased the intestinal absorption of 2 mg/kg MRK-1 maximally by approximately 30 to 40%, and a major component of the interaction likely resulted from its reduced systemic clearance via the inhibition of CYP3A isozymes. Oral coadministration of quinidine (10 and 30 mg/kg) increased both the extent and the first-order rate of absorption of MRK-1 (2 mg/kg) by approximately 40 to 50% and approximately 100 to 300%, respectively, in rats, thus further substantiating the role of P-gp in modulating the intestinal absorption of MRK-1 in this species. At the 10 mg/kg MRK-1 dose, however, the entire increase in its AUC upon coadministration with ritonavir or quinidine could be attributed to a reduced systemic clearance, and no effects on intestinal absorption were apparent. In contrast to rats, the effects of P-gp in determining the intestinal absorption of MRK-1 appeared less significant in rhesus monkeys at either dose.     

Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir

OBJECTIVES: Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. METHODS: In a randomized, placebo-controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis. RESULTS: When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26%+/-16% (P > .05) lower in CYP2C19*1/*2 individuals and 66%+/-14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354+/-173 mL/min versus 202+/-139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463+/-168 mL/min versus 305+/-112 mL/min [P = .023] for *1/*1, 343+/-127 mL/min versus 190+/-93 mL/min [P = .008] for *1/*2, and 158+/-54 mL/min versus 22+/-11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism. CONCLUSIONS: Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients.     

An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir

BACKGROUND: Depression often coexists with a number of disease states, and patients with a diagnosis of depression often receive multiple medications. Thus, it is desirable to avoid coadministration of agents that have a potential for drug interactions in these patients. Although escitalopram and its metabolites are weak to negligible inhibitors of the cytochrome P450 (CYP) 3A4 isozyme and are therefore unlikely to affect plasma concentrations of ritonavir (a CYP3A4 substrate and prototype CYP3A4 inhibitor), ritonavir may potentially affect plasma concentrations of escitalopram, as CYP3A4 is partially responsible for conversion of escitalopram to its major metabolite, S-demethylcitalopram (S-DCT). OBJECTIVES: The aim of this study was to investigate the potential for pharmacokinetic interaction between escitalopram and ritonavir after concomitant administration of a single dose of each in healthy young subjects. METHODS: In this single-center, randomized, open-label, 3-way crossover study, subjects received each of the following: a single dose of escitalopram 20 mg, a single dose of ritonavir 600 mg, and single doses of both escitalopram 20 mg and ritonavir 600 mg. Blood was collected and plasma was analyzed for the pharmacokinetic parameters (maximum plasma concentration [C(max)], time to C(max) [T(max)], area under the plasma concentration-time curve, plasma elimination half-life, oral clearance, and apparent volume of distribution) of escitalopram, S-DCT, and ritonavir. RESULTS: Of 21 subjects (11 men, 10 women; mean [SD] age, 28.4 [4.4] years) who were enrolled, 18 completed the study. After concomitant administration of escitalopram and ritonavir, no statistically significant differences were noted in the pharmacokinetics of escitalopram, with the exception of apparent volume of distribution, which was reduced by approximately 10% (P < 0.001). The pharmacokinetics of S-DCT were unaffected by coadministration of ritonavir, with the exception of T(max), which was increased in the presence of ritonavir. The pharmacokinetic parameters of ritonavir were also unaffected by coadministration of escitalopram. CONCLUSION: In general, no pharmacokinetic interaction was observed between escitalopram and ritonavir in the present study.     

Pharmacokinetics of the triazole antifungal agent genaconazole in healthy men after oral and intravenous administration.

The pharmacokinetics of genaconazole, a potent new difluorophenyl-triazole antifungal agent, was studied in 12 healthy male volunteers following a single oral or intravenous administration of the drug. In a randomized two-way crossover design, each volunteer received either two 50-mg genaconazole tablets orally or a parenteral preparation containing 100 mg of genaconazole given as a 30-min intravenous infusion. Both dosage regimens were well tolerated. Blood and urine samples were collected up to 10 days after drug administration. Concentrations of genaconazole in plasma and urine were determined by a specific high-performance liquid chromatography assay with a limit of quantitation of 0.1 microgram/ml. Pharmacokinetic evaluation following oral and intravenous doses indicated that mean values for the area under the concentration-time curve from 0 h to infinity (137 and 136 micrograms.h/ml), half-life (50 and 49 h), volume of distribution (52 and 52 liters), and clearance (12 and 12 ml/min) were independent of the route of drug administration. The oral and intravenous administrations of genaconazole yielded virtually superimposable plasma concentration-time curves, resulting in an absolute bioavailability of 100%. Amounts of unchanged genaconazole found in urine samples from 0 to 240 h after oral and intravenous doses were comparable, and urinary excretion accounted for 76 and 78% of the administered dose, respectively. Renal clearances for the two routes of administration were also similar, and renal clearance accounted for over 80% of the total body clearance. The 100% absolute bioavailability of genaconazole regardless of the route of administration provides greater dosing flexibility in various clinical settings than currently exists.     

Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40

BACKGROUND: The pharmacokinetics of digoxin is modulated by the efflux pump P-glycoprotein. Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative used to improve the solubilization of drugs and vitamins, has been shown to inhibit this membrane transporter in vitro and in vivo. So far, no study in humans has evaluated the effect of Cremophor RH40 (BASF Aktiengesellschaft) (polyoxyl 40 hydrogenated castor oil) on P-glycoprotein. METHODS: A randomized, double-blind, placebo-controlled crossover study in 12 healthy individuals was performed with a single oral dose of 0.5 mg digoxin in a hard gelatin capsule in combination with multiple doses of oral Cremophor RH40 (600 mg 3 times daily) or placebo. A digitized electrocardiogram with 12 standard leads was recorded to assess the pharmacodynamics of digoxin. RESULTS: Cremophor RH40 delayed and enhanced the absorption of digoxin in the first 5 hours after dosing. During Cremophor RH40 administration, digoxin lag time was significantly prolonged compared with placebo (0.53 +/- 0.25 hour versus 0.36 +/- 0.19 hour, P =.04). The peak concentration of digoxin increased by 22%, from 2.21 +/- 0.94 ng/mL to 2.69 +/- 1.28 ng/mL (P =.06). Similarly, the area under the plasma concentration-time curve from 0 to 5 hours significantly increased by 22% (5.23 +/- 1.63 h. ng/mL versus 4.30 +/- 1.12 h. ng/mL, P =.03). Digoxin did not cause a clinically significant change in the dynamic parameters during both periods. CONCLUSION: This study demonstrates a pharmacokinetic and pharmaceutic interaction between the emulgent Cremophor RH40 and digoxin, caused by P-glycoprotein inhibition and prolongation of the dissolution time of digoxin tablets by Cremophor RH40, respectively. Our in vivo study in humans supports the validity of in vitro observations on P-glycoprotein.     

Pharmacokinetics of ceftriaxone in patients with typhoid fever.

Ceftriaxone in short courses has emerged as an effective alternative to chloramphenicol for the treatment of typhoid fever. To study the pharmacokinetics of ceftriaxone in acute typhoid fever, 10 febrile Nepalese adolescents and young adults with blood culture-positive illness were treated with 3 g of ceftriaxone (intravenous infusion for 30 min) daily for 3 days. On the 1st and 3rd day of treatment, blood and urine samples were collected at defined intervals for measurements of drug concentrations. Kinetic parameters including concentrations at the end of infusion (Cmax) and 24 h after the end of infusion (Cmin), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), total plasma clearance, renal clearance, percentage excreted in urine, and volume of distribution were estimated. On day 1, mean values were as follows: Cmax, 291 micrograms/ml; Cmin, 21.7 micrograms/ml; plasma t1/2, 5.2 h; AUC, 1,428 micrograms.h/ml; total plasma clearance, 37 ml/min; renal clearance, 19 ml/min; percentage excreted in urine, 49.7%; and volume of distribution, 16.1 liters. Mean values on day 3 were not significantly different from those on day 1. Compared with published values for healthy volunteers who received the same dose, our mean t1/2s and AUCs were lower and our mean total plasma clearances, renal clearances, and volumes of distribution were higher. The good clinical responses of these patients to therapy and the adequate Cmins support the use of ceftriaxone once daily for the treatment of typhoid fever.     

Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance

BACKGROUND: Gemfibrozil increases the plasma concentrations of active acid forms of cerivastatin, lovastatin, and simvastatin. Pravastatin pharmacokinetics differs from those of these 3 statins, which are extensively metabolized. Our aim was to study the effects of gemfibrozil on the pharmacokinetics of pravastatin. METHODS: A randomized, placebo-controlled, 2-phase crossover study was carried out. Ten healthy volunteers took gemfibrozil (1200 mg/d) or placebo for 3 days. On day 3, each subject ingested a single 40-mg dose of pravastatin. The concentrations of pravastatin and gemfibrozil in plasma and the cumulative excretion of pravastatin into urine were measured up to 24 hours. RESULTS: During the gemfibrozil phase, the mean total area under the plasma concentration-time curve (AUC) of pravastatin from 0 hours to infinity was 202% (range, 40%-412%) of the corresponding value during the placebo phase (P <.05), but there was no difference in the half-life between the phases. The renal clearance of pravastatin was reduced from 25 L/h to 14 L/h by gemfibrozil (P <.0001), but the cumulative excretion of pravastatin into urine did not change significantly. The increase in the AUC of pravastatin from 0 to 24 hours correlated significantly with the decrease in the renal clearance of pravastatin (r = 0.72, P =.02). However, the change in renal clearance was only a minor contributor to the increase in pravastatin AUC. CONCLUSIONS: Gemfibrozil increases plasma concentrations of pravastatin. This is partly but not solely the result of the reduced renal clearance of pravastatin. The increase in pravastatin AUC from 0 hours to infinity by gemfibrozil may represent an interference with a transport protein.     

Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition

BACKGROUND: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate. OBJECTIVES: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T). Material and methods: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects. RESULTS: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes. CONCLUSION: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.