John Grundy - Academia.edu (original) (raw)

Papers by John Grundy

Pulmonary circulation, Apr 1, 2020

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being de... more Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n ¼ 32) and multiple ascending dose (n ¼ 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 mg (single dose), but not 200 mg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0-1.5 h post-dose and mean terminal elimination half-life values from 20.5-26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34-4.49 (QD dosing) and 1.95-2.36 (BID dosing). Mean effective half-life values ranged from 17.5-18.4 h, reflecting 1.7−fold(QDdosing)and1.7-fold (QD dosing) and 1.7−fold(QDdosing)and2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediaterelease ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

Lancet (London, England), Feb 18, 2017

miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this stud... more miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes. In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using...

Nephrology Dialysis Transplantation, 2016

Journal of Crohn's and Colitis

Background Etrasimod is an oral, selective sphingosine 1-phosphate receptor modulator in clinical... more Background Etrasimod is an oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders, including ulcerative colitis, Crohn’s disease, and eosinophilic esophagitis. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of etrasimod. Methods This single-dose, open-label, parallel-group study included 36 adult subjects (aged 18-80 years; body mass index ≥18 kg/m2) with hepatic impairment, based on Child-Pugh score at screening (mild=5 to 6 [n=8], moderate=7 to 9 [n=8], severe=10 to 14 [n=6]), and their demographically matched control subjects with normal hepatic function (n=14 total). The first subject with severe hepatic impairment was enrolled after ≥2 subjects with mild and ≥2 subjects with moderate hepatic impairment had been enrolled and followed for ≥48 hours after dosing to ensure no observed significant safety signals. On Day 1, subjec...

Nephrology Dialysis Transplantation, 2016

Journal of Pharmacology and Experimental Therapeutics, 2014

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survi... more Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.

Molecular therapy. Nucleic acids, Jan 20, 2015

Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological an... more Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2'-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between...

Journal of Pediatric Gastroenterology and Nutrition, 2005

Background: Although IgA endomysial antibodies (EMA) and tissue transglutaminase (TG) are sensiti... more Background: Although IgA endomysial antibodies (EMA) and tissue transglutaminase (TG) are sensitive and specific serologic tests for the diagnosis of celiac disease, there is limited information on the association of the magnitude of antibody level with the severity of the histological abnormalities of the intestine. Purpose: To determine if EMA and TG titers correlate with the severity of histological changes in patients with celiac disease. Methods: We identified 148 children from our laboratory database that had EMA, TG and intestinal biopsies performed. IgA EMA was determined by indirect immunofluorescence with results expressed as a dilutional titer with positivity determined at 1:5. IgA TG was determined by an enzyme linked human immunosorbent ELISA assay with results expressed in standardized units. A modified Marsh histological grading system was used to describe the duodenal biopsies: Type 0 normal, I increased intraepithelial lymphocytes (IEL), II hyperplastic crypts, IIIa partial villus atrophy, IIIb subtotal villus atrophy, IIIc total villous atrophy. Results: Mean values for EMA (Table 1) and TG (Table 2) progressively increased with increasing Marsh score. Conclusion: There was considerable variability in EMA and TG levels for each Marsh grade, so that an individual level could not be utilized to predict histological severity. The data show that as a group, increasing severity of the histological lesion in celiac disease was associated with increased levels of both IgA EMA and TG antibodies.

Journal of Controlled Release, 1997

Significant daily variability occurs in the bioavailability and peak plasma concentrations of nif... more Significant daily variability occurs in the bioavailability and peak plasma concentrations of nifedipine given as an immediate-release (IR) oral dosage form, which is attributed to increased absorption or reduced presystemic metabolism in the morning. The nifedipine gastrointestinal ...

Epilepsy Research, 2004

Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential e... more Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential effects of zonisamide on carbamazepine pharmacokinetics (PK) have not been well characterized, with contradictory literature reports. Hence, an in vitro study was designed to evaluate the cytochrome P450 inhibition spectrum of zonisamide using human liver microsomes. Further, an in vivo steady-state study was performed to measure the effect of zonisamide on carbamazepine PK in epileptic patients, and monitor zonisamide PK. In vitro human liver microsomes were incubated with zonisamide (200, 600 or 1000 microM) in the presence of appropriate probe substrates to assess selected cytochrome P450 activities. In vivo, the effect of zonisamide, up to 400 mg/day, on the steady-state PK of carbamazepine and carbamazepine-epoxide (CBZ-E) was studied in 18 epileptic patients. In vitro, zonisamide did not inhibit CYP1A2 and 2D6, and only weakly inhibited CYP2A6, 2C9, 2C19, and 2E1. The estimated Ki for zonisamide inhibition of CYP3A4 was 1076 microM, 12 times higher than typical unbound therapeutic serum zonisamide concentrations. In vivo, no statistically significant differences were observed for mean Cmax, Tmax, and AUC0-12 of total and free carbamazepine and CBZ-E measured before and after zonisamide administration (300-400 mg/day for 14 days). However, CBZ-E renal clearance was significantly (p < 0.05) reduced by zonisamide. The observed mean zonisamide t1/2 (36.3h), relative to approximately 65 h reported in subjects on zonisamide monotherapy, reflects known CYP3A4 induction by carbamazepine. Based on the lack of clinically relevant in vitro and in vivo effects, adjustment of carbamazepine dosing should not be required with concomitant zonisamide administration.

Biopharmaceutics & Drug Disposition, 1998

Previous studies with rats indicate that nifedipine undergoes both hepatic and extrahepatic presy... more Previous studies with rats indicate that nifedipine undergoes both hepatic and extrahepatic presystemic metabolism after peroral (po) administration, and that its bioavailability is increased and absorption delayed by concomitant administration of grapefruit juice concentrate (GJC). Hence, the effects of GJC could be to delay stomach emptying and inhibit nifedipine metabolism in the small-intestinal wall and liver or, alternatively, to impede nifedipine absorption until reaching the large intestine where gut wall presystemic metabolism is not a factor. The mechanism(s) of action of GJC might be partially resolved by comparison with orange juice concentrate (OJC), which has a similar consistency but lacks inhibitory effects on nifedipine presystemic metabolism, and also by giving regular-strength solutions of the two juices, both on which should not significantly affect stomach emptying. This study compared the po bioavailability of nifedipine (6 mg kg-1) in male Sprague-Dawley rats coadministered GJC, OJC, grapefruit juice regular strength (GJRS), orange juice regular strength (OJRS), or (tap) water. Nifedipine plasma concentration-time profiles in the GJRS, OJRS, and (tap) water groups displayed a single peak. Both GJC and OJC groups have double-peak profiles (indicating delayed gastric emptying); however, the majority of the nifedipine dose in both cases was absorbed during the interval of the second peak, which occurred several hours postdosing. GJC significantly increased nifedipine bioavailability (relative bioavailability 2.02, compared with (tap) water), indicating that GJC may affect both extrahepatic and hepatic first-pass metabolism, although a reduction in systemic nifedipine clearance cannot be ruled out. Surprisingly, GJRS had no significant effect on nifedipine bioavailability. OJC did not increase nifedipine bioavailability, further suggesting that the delay in nifedipine absorption by GJC or OJC results from delayed gastric emptying.

The American Journal of Cardiology, 1989

Biopharmaceutics & Drug Disposition, 1997

The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the... more The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first-pass effect after p.o. dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first-pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (i.c.), and intraperitoneal (i.p.) routes of administration were compared to that for an intravenous (i.v.) dose (in each case a dose of 6 mg kg-1 was given) using adult male Sprague-Dawley rats (249-311 g, n = 6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after i.v. dosing was 10.3 mL min-1 kg-1. The nifedipine blood-to-plasma ratio was found to be about 0.59. Therefore, the systemic blood clearance of nifedipine was about 17.5 mL min-1 kg-1; which, compared to the hepatic blood flow of rats (55 to 80 mL min-1 kg-1) showed that nifedipine is poorly extracted by the liver (0.22 < or = EH < = 0.32). The mean absolute bioavailabilities of the p.o., i.p., and i.c. doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat.

Pulmonary circulation, Apr 1, 2020

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being de... more Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n ¼ 32) and multiple ascending dose (n ¼ 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 mg (single dose), but not 200 mg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0-1.5 h post-dose and mean terminal elimination half-life values from 20.5-26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34-4.49 (QD dosing) and 1.95-2.36 (BID dosing). Mean effective half-life values ranged from 17.5-18.4 h, reflecting 1.7−fold(QDdosing)and1.7-fold (QD dosing) and 1.7−fold(QDdosing)and2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediaterelease ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

Lancet (London, England), Feb 18, 2017

miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this stud... more miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes. In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using...

Nephrology Dialysis Transplantation, 2016

Journal of Crohn's and Colitis

Background Etrasimod is an oral, selective sphingosine 1-phosphate receptor modulator in clinical... more Background Etrasimod is an oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders, including ulcerative colitis, Crohn’s disease, and eosinophilic esophagitis. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of etrasimod. Methods This single-dose, open-label, parallel-group study included 36 adult subjects (aged 18-80 years; body mass index ≥18 kg/m2) with hepatic impairment, based on Child-Pugh score at screening (mild=5 to 6 [n=8], moderate=7 to 9 [n=8], severe=10 to 14 [n=6]), and their demographically matched control subjects with normal hepatic function (n=14 total). The first subject with severe hepatic impairment was enrolled after ≥2 subjects with mild and ≥2 subjects with moderate hepatic impairment had been enrolled and followed for ≥48 hours after dosing to ensure no observed significant safety signals. On Day 1, subjec...

Nephrology Dialysis Transplantation, 2016

Journal of Pharmacology and Experimental Therapeutics, 2014

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survi... more Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre-mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development.

Molecular therapy. Nucleic acids, Jan 20, 2015

Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological an... more Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2'-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between...

Journal of Pediatric Gastroenterology and Nutrition, 2005

Background: Although IgA endomysial antibodies (EMA) and tissue transglutaminase (TG) are sensiti... more Background: Although IgA endomysial antibodies (EMA) and tissue transglutaminase (TG) are sensitive and specific serologic tests for the diagnosis of celiac disease, there is limited information on the association of the magnitude of antibody level with the severity of the histological abnormalities of the intestine. Purpose: To determine if EMA and TG titers correlate with the severity of histological changes in patients with celiac disease. Methods: We identified 148 children from our laboratory database that had EMA, TG and intestinal biopsies performed. IgA EMA was determined by indirect immunofluorescence with results expressed as a dilutional titer with positivity determined at 1:5. IgA TG was determined by an enzyme linked human immunosorbent ELISA assay with results expressed in standardized units. A modified Marsh histological grading system was used to describe the duodenal biopsies: Type 0 normal, I increased intraepithelial lymphocytes (IEL), II hyperplastic crypts, IIIa partial villus atrophy, IIIb subtotal villus atrophy, IIIc total villous atrophy. Results: Mean values for EMA (Table 1) and TG (Table 2) progressively increased with increasing Marsh score. Conclusion: There was considerable variability in EMA and TG levels for each Marsh grade, so that an individual level could not be utilized to predict histological severity. The data show that as a group, increasing severity of the histological lesion in celiac disease was associated with increased levels of both IgA EMA and TG antibodies.

Journal of Controlled Release, 1997

Significant daily variability occurs in the bioavailability and peak plasma concentrations of nif... more Significant daily variability occurs in the bioavailability and peak plasma concentrations of nifedipine given as an immediate-release (IR) oral dosage form, which is attributed to increased absorption or reduced presystemic metabolism in the morning. The nifedipine gastrointestinal ...

Epilepsy Research, 2004

Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential e... more Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential effects of zonisamide on carbamazepine pharmacokinetics (PK) have not been well characterized, with contradictory literature reports. Hence, an in vitro study was designed to evaluate the cytochrome P450 inhibition spectrum of zonisamide using human liver microsomes. Further, an in vivo steady-state study was performed to measure the effect of zonisamide on carbamazepine PK in epileptic patients, and monitor zonisamide PK. In vitro human liver microsomes were incubated with zonisamide (200, 600 or 1000 microM) in the presence of appropriate probe substrates to assess selected cytochrome P450 activities. In vivo, the effect of zonisamide, up to 400 mg/day, on the steady-state PK of carbamazepine and carbamazepine-epoxide (CBZ-E) was studied in 18 epileptic patients. In vitro, zonisamide did not inhibit CYP1A2 and 2D6, and only weakly inhibited CYP2A6, 2C9, 2C19, and 2E1. The estimated Ki for zonisamide inhibition of CYP3A4 was 1076 microM, 12 times higher than typical unbound therapeutic serum zonisamide concentrations. In vivo, no statistically significant differences were observed for mean Cmax, Tmax, and AUC0-12 of total and free carbamazepine and CBZ-E measured before and after zonisamide administration (300-400 mg/day for 14 days). However, CBZ-E renal clearance was significantly (p < 0.05) reduced by zonisamide. The observed mean zonisamide t1/2 (36.3h), relative to approximately 65 h reported in subjects on zonisamide monotherapy, reflects known CYP3A4 induction by carbamazepine. Based on the lack of clinically relevant in vitro and in vivo effects, adjustment of carbamazepine dosing should not be required with concomitant zonisamide administration.

Biopharmaceutics & Drug Disposition, 1998

Previous studies with rats indicate that nifedipine undergoes both hepatic and extrahepatic presy... more Previous studies with rats indicate that nifedipine undergoes both hepatic and extrahepatic presystemic metabolism after peroral (po) administration, and that its bioavailability is increased and absorption delayed by concomitant administration of grapefruit juice concentrate (GJC). Hence, the effects of GJC could be to delay stomach emptying and inhibit nifedipine metabolism in the small-intestinal wall and liver or, alternatively, to impede nifedipine absorption until reaching the large intestine where gut wall presystemic metabolism is not a factor. The mechanism(s) of action of GJC might be partially resolved by comparison with orange juice concentrate (OJC), which has a similar consistency but lacks inhibitory effects on nifedipine presystemic metabolism, and also by giving regular-strength solutions of the two juices, both on which should not significantly affect stomach emptying. This study compared the po bioavailability of nifedipine (6 mg kg-1) in male Sprague-Dawley rats coadministered GJC, OJC, grapefruit juice regular strength (GJRS), orange juice regular strength (OJRS), or (tap) water. Nifedipine plasma concentration-time profiles in the GJRS, OJRS, and (tap) water groups displayed a single peak. Both GJC and OJC groups have double-peak profiles (indicating delayed gastric emptying); however, the majority of the nifedipine dose in both cases was absorbed during the interval of the second peak, which occurred several hours postdosing. GJC significantly increased nifedipine bioavailability (relative bioavailability 2.02, compared with (tap) water), indicating that GJC may affect both extrahepatic and hepatic first-pass metabolism, although a reduction in systemic nifedipine clearance cannot be ruled out. Surprisingly, GJRS had no significant effect on nifedipine bioavailability. OJC did not increase nifedipine bioavailability, further suggesting that the delay in nifedipine absorption by GJC or OJC results from delayed gastric emptying.

The American Journal of Cardiology, 1989

Biopharmaceutics & Drug Disposition, 1997

The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the... more The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first-pass effect after p.o. dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first-pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (i.c.), and intraperitoneal (i.p.) routes of administration were compared to that for an intravenous (i.v.) dose (in each case a dose of 6 mg kg-1 was given) using adult male Sprague-Dawley rats (249-311 g, n = 6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after i.v. dosing was 10.3 mL min-1 kg-1. The nifedipine blood-to-plasma ratio was found to be about 0.59. Therefore, the systemic blood clearance of nifedipine was about 17.5 mL min-1 kg-1; which, compared to the hepatic blood flow of rats (55 to 80 mL min-1 kg-1) showed that nifedipine is poorly extracted by the liver (0.22 < or = EH < = 0.32). The mean absolute bioavailabilities of the p.o., i.p., and i.c. doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat.