Pharmacology I - Pharmacokinetics - Absorption Part 2 PDF

PHARMACOLOGY I PHARMACOKINETICS ABSORPTION part 2 Boni Singu Roger K. Verbeeck, Ph.D. School of Pharmacy UNAM [email protected]  CONTENTS Ø Oraladministration. Ø Absolute and relative bioavailability. Ø First-pass effect. Ø Tran...

PHARMACOLOGY I PHARMACOKINETICS ABSORPTION part 2 Boni Singu Roger K. Verbeeck, Ph.D. School of Pharmacy UNAM [email protected]  CONTENTS Ø Oraladministration. Ø Absolute and relative bioavailability. Ø First-pass effect. Ø Transporters. Ø Modified-release formulations. 1  ORAL ABSORPTION oral dose biophase body distribution absorption elimination GIT blood distribution tissues/organs Following oral administration, the drug is absorbed from the GIT (small intestine) and arrives in the general circulation. From the blood the drug reversibly distributes into organs and tissues including the liver and the kidney, the two organs responsible for the elimination of the drug from the body. 2  ORAL ABSORPTION Tmax = Tmax ≠ AUC ≠ AUC = Cmax ≠ Cmax ≠ Cmax AUC ≡ extent of therapeutic window therapeutic window absorption Tmax ≡ rate of absorption Cmax ≡ both extent and rate of absorption Tmax Tmax Both extent (fraction of the dose absorbed) and rate (speed) of absorption influence the plasma concentration-time profile of a drug and hence therapeutic efficacy and safety. Tmax is mainly determined by rate, AUC (area under the Cp- time curve) by extent, and Cmax by both rate and extent of absorption. 3  BIOAVAILABILITY ØThe term bioavailability (F) is often used to express the completeness or extent of absorption. ØIn official guidelines (FDA, EMA) bioavailability is defined as the “rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action”. ØAbsolute availability versus relative availability. 4  ORAL ABSORPTION absolute bioavailability 𝐴𝑈𝐶!"#$ 𝐷𝑜𝑠𝑒%& 𝐹= × 𝐴𝑈𝐶%& 𝐷𝑜𝑠𝑒!"#$ F is an absolute measure of the extent iv of absorption of the drug (in intact nasal form) into the systemic circulation. oral AUC is a measure of exposure of the patient to the drug substance. 5  ORAL ABSORPTION relative bioavailability 𝐴𝑈𝐶(')( 𝐹"'$#(%&' = 𝐴𝑈𝐶"'* Frel is a comparative measure of extent of absorption between two different formulations. In a bioequivalence (BE) study the bioavailability of a test medicinal product (e.g. the generic LOVRAK®) is compared to the bioavailability of a reference medicinal product (ZOVIRAX®). A BE study is a relative bioavailability study. 6  ORAL BIOAVAILABILITY oral due to the action drug metabolizing gut wall and hepatic first-pass effect dose enzymes/transporters expressed in (FPE) = presystemic elimination the gut wall and the liver gut lumen gut wall T Transporter CYP450 liver T T CYP450 CYP450 (cytochrome P450): an important superfamily of drug metabolising enzymes 7  ORAL ABSORPTION cyclosporine Fa=0.86 X FG=0.41 X FH=0.76 F=0.27 F = Fa × FG × FH EG=0.59 EH=0.24 CYP3A CYP450 3A subfamily CYP3A P P-glycoprotein P CYP3A 0.86 0.35 0.27 EG: gut wall extraction ratio EH: hepatic extraction ratio 0.35 x 0.24 = 0.084 8% 0.86 x 0.59 = 0.507 73% of the oral dose 14% 51% does not reach the 14 + 51 + 8 = 73% systemic circulation 8  ABSOLUTE BIOAVAILABILITY ØA drug, following its oral administration, must pass sequentially from the GIT lumen, through the gut wall and the liver before entering the systemic circulation. F = Fa × FG × FH Ø Fa : fraction of the orally administered dose neither lost in the faeces nor decomposed in the GIT lumen. Ø FG and FH: fraction of the absorbed dose passing through the gut wall and liver, respectively, and escaping extraction. 9  ORAL ABSORPTION first-pass effect met = metabolite tac = tacrolimus portal vein intestinal mucosa cells (enterocytes) gut lumen TACROLIMUS oral dose Tacrolimus, an immunosuppressive agent, has an oral bioavailability (F) of approximately 15%. The reasons for this incomplete oral bioavailability are P-gp mediated efflux of tacrolimus and CYP3A catalyzed metabolism. 10  ORAL ABSORPTION first-pass effect Bioavailabilities of various substrates of CYP3A across the gut wall and the liver. F = Fa × FG × FH Fa Fa = fraction of an oral dose that diffuses (or is transported) from the gut lumen into the gut wall (enterocytes) FG = 1 – EG and FH = 1 - EH EG and EH are the gut wall and hepatic extraction ratios (or extraction coefficients), respectively. 11  100% Felodipine 15% 45%* Felodipine dose Felodipine is a calcium bioavailability channel antagonist used for the treatment of hypertension. Liver control GJ Portal vein EG = 0.7 EG = 0.1 100% FG = 0.3 FG = 0.9 Gut lumen Small bowel A B Sinusoid EH = 0.5 EH = 0.5 Enterocyte CYP3A4 30% Hepatocyte 45%* FH = 0.5 FH = 0.5 100% 15% 90%* CYP3A4 Inhibition 30% Foral = 0.15 Foral = 0.45 Grapefruit juice 90%* Figure 1. First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its Interaction with Grapefruit Juice. Wilkinson GR: Drug metabolism CYP3A enzymes (e.g., CYP3A4) present in enterocytes of the intestinal epithelium extensively metabolize felodipine during its absorption, and variability among patients and on average only 30 percent of the administered dose enters the portal vein (solid line). Subsequently, CYP3A enzymes in the liver further metabolize the drug so that only 15 percent of the dose is bioavailable and finally reaches the systemic circulation and is able to exert its ef- in drug response. N Engl J Med fects. Grapefruit juice selectively inhibits CYP3A in the enterocyte, with the net result being an increase in the oral bioavailability of felodipine 352: 2211-2221, 2005. 12 by a factor of three, denoted by the asterisks and the dashed lines.  ORAL ABSORPTION first pass effect Examples of drugs showing saturable first-pass metabolism in the liver and/or gut wall after oral administration of therapeutic doses. Morphine Severe/chronic pain 13  SUMMARY OF PRODUCT CHARACTERISTICS MST® CONTINUS® 5 mg,10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg prolonged release tablets containing morphine sulphate. Patients receiving MST CONTINUS tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required. https://www.medicines.org.uk/emc/medicine/1223 14  ORAL ABSORPTION low intestinal permeability Examples of drugs showing low bioavailability because of low intestinal absorption (low permeability). Aminoglycosides are not absorbed following oral administration. They have to be injected (iv, im) when used to treat bacterial infections. However, they may be used orally to treat bacterial gastroenteritis, and to “prepare” the bowel for surgery. 15  ORAL ABSORPTION transporters CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 71, NUMBER 1 Dresser et al 15 Mean plasma fexofenadine concentration-time profiles following oral administration of 120 mg fexofenadine to 10 healthy subjects: with 300 ml water, grapefruit juice at 25% of regular strength (25% GFJ), grapefruit juice (GFJ), orange juice (OJ), or apple juice (AJ) followed by 150 ml of the same fluid every 0.5 to 3 hours (total volume, 1.2 L). Fig 3. Mean plasma fexofenadine concentration–time pro- Fig 4. Change in area under the plasma fexofenadine con- files for persons (n = 10) orally administered fexofenadine centration–time profile from 0 to 8 hours [AUC(0-8)] with 16 (120 mg) with 300 ml water, grapefruit juice at 25% of regu- 25% regular-strength grapefruit juice (25% GFJ), grapefruit  ORAL ABSORPTION transporters fexofenadine + - zwitterion The oral absorption of fexofenadine, a zwitterion, P-gp OATP MRP2 GI lumen across the intestinal epithelium seems to be mediated by OATP2B1 (influx at the apical side) and MRP3 MRP3 blood circulation (efflux at the basolateral side). Ming et al.: Vectorial transport of fexofenadine across Caco-2 cells – involvement of apical uptake and basolateral efflux transporters. Mol. Pharmaceut. 8: 1677-1686, 2011. 17  ABSORPTION extent of absorption Examples of reactions within the GIT that compete for drug absorption from solution (meaning the drug dissolution is not the rate limiting step). complexation quinolones polyvalent cations adsorption furosemide cholestyramine hydrolysis penicillin G acid hydrolysis erythromycin acid hydrolysis insulin by peptidases 1st pass effect cyclosporin by CYP3A isoproterenol by sulfoconjugation efflux pump cyclosporin P-glycoprotein 18 EXTENDED RELEASE FORMULATIONS Mean steady state (Day 6) plasma concentration-time profiles of tolterodine (muscarinic receptor antagonist used in urinary incontinence) in 13 patients treated with tolterodine immediate release (IR) tablets 2 mg twice daily or extended release (ER) capsules 4 mg once-daily. Olsson and Szamosi: Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine. Clin. Pharmacokinet. 40: 227-235, 2001. 19 ENTERIC-COATED FORMULATIONS fasting fed N=8 N=5 N=3 lag time Salicylate plasma concentration-time profiles following administration of enteric-coated ASA tablets (single unit formulation, 2 x 500 mg) to healthy volunteers: A, on an empty stomach; B, after a meal. 20